Molecule Information

General Information of the Molecule (ID: Mol00061)

• Name: Epidermal growth factor receptor (EGFR) ,Homo sapiens
• Synonyms: Proto-oncogene c-ErbB-1; Receptor tyrosine-protein kinase erbB-1; ERBB; ERBB1; HER1
• Molecule Type: Protein
• Gene Name: EGFR
• Gene ID: 1956
• Location: chr7:55019017-55211628[+]
• Sequence:
  MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEV
  VLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALA
  VLSNYDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDF
  QNHLGSCQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGC
  TGPRESDCLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYV
  VTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFK
  NCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAF
  ENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKL
  FGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCN
  LLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVM
  GENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVV
  ALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGS
  GAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGI
  CLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAA
  RNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSY
  GVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPK
  FRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQ
  QGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTED
  SIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLN
  TVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRV
  APQSSEFIGA
• Function: Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin. Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration. Plays a role in enhancing learning and memory performance.
• Uniprot ID: EGFR_HUMAN
• Ensembl ID: ENSG00000146648
• HGNC ID: HGNC:3236

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 25 drug(s) in total

Afatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [1], [2], [3]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Afatinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Exon sequencing assay
• Experiment for Drug Resistance: Progression-free and post-progression survival asaay
• Mechanism Description: T790M was detected in half of the lung adenocarcinoma after acquiring resistance to afatinib. T790M is still the major acquired resistance mechanism. First-generation EGFR TkI exposure did not influence the prevalence of T790M in lung cancer acquired resistance to afatinib.

Disease Class: Non-small cell lung cancer [4], [5], [6]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Afatinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Directional sequencing assay; Direct sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Progression-free and post-progression survival asaay; Analysis of progression-free survival (PFS) assay; Overall survival assay
• Mechanism Description: The identification of T790M as acquired resistance mechanism was clinically feasible. Although T790M had no prognostic or predictive role in the present study, further research is necessary to identify patients with T790M-mutant tumors who might benefit from newly developed T790M-specific TkIs.T790M is likely a common resistance mechanism in patients treated with first-line afatinib. Although repeat biopsies at progression are crucial in elucidating resistance mechanisms, this study suggests that clinical and technical issues often limit their feasibility, highlighting the importance of developing.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Esophagogastric cancer [7]

• Sensitive Disease: Esophagogastric cancer [ICD-11: 2B71.1]
• Sensitive Drug: Afatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: In summary, we find that concurrent amplification of EGFR and ERBB2 is associated with response to the HER kinase inhibitor afatinib in patients with trastuzumab-refractory EG cancer. Heterogeneous uptake of 89Zr-trastuzumab measured noninvasively by PET was associated with disease progression. Analyses of multiple disease sites sampled at the time of disease progression indicated several potential mediators of afatinib resistance, including loss of EGFR amplification and gain of MET amplification.

Brigatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Solid tumour/cancer [8]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Brigatinib
• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: SUP-M2 cells; Colon; Homo sapiens (Human); CVCL_2209
• In Vitro Model: KARPAS-299 cells; Peripheral blood; Homo sapiens (Human); CVCL_1324
• In Vitro Model: SU-DHL-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0538
• In Vitro Model: L-82 cells; Pleural effusion; Homo sapiens (Human); CVCL_2098
• In Vitro Model: HCC78 cells; Pleural effusion; Homo sapiens (Human); CVCL_2061
• In Vitro Model: H838 cells; Lymph node; Homo sapiens (Human); CVCL_1594
• In Vitro Model: H-4-II-E cells; Liver; Rattus norvegicus (Rat); CVCL_0284
• In Vitro Model: H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: H2228 cells; Lung; Homo sapiens (Human); CVCL_1543
• In Vitro Model: DEL cells; Pleural effusion; Homo sapiens (Human); CVCL_1170
• In Vivo Model: SCID beige mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Brigatinib is the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses.

Disease Class: Solid tumour/cancer [8]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Brigatinib
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: SUP-M2 cells; Colon; Homo sapiens (Human); CVCL_2209
• In Vitro Model: KARPAS-299 cells; Peripheral blood; Homo sapiens (Human); CVCL_1324
• In Vitro Model: SU-DHL-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0538
• In Vitro Model: L-82 cells; Pleural effusion; Homo sapiens (Human); CVCL_2098
• In Vitro Model: HCC78 cells; Pleural effusion; Homo sapiens (Human); CVCL_2061
• In Vitro Model: H838 cells; Lymph node; Homo sapiens (Human); CVCL_1594
• In Vitro Model: H-4-II-E cells; Liver; Rattus norvegicus (Rat); CVCL_0284
• In Vitro Model: H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: H2228 cells; Lung; Homo sapiens (Human); CVCL_1543
• In Vitro Model: DEL cells; Pleural effusion; Homo sapiens (Human); CVCL_1170
• In Vivo Model: SCID beige mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Brigatinib is the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses.

Cetuximab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Colorectal cancer [9]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Cetuximab
• Molecule Alteration: Missense mutation; p.G465E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Colon cells; Colon; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsy assay
• Mechanism Description: Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Disease Class: Metastatic colorectal cancer [10]

• Resistant Disease: Metastatic colorectal cancer [ICD-11: 2D85.0]
• Resistant Drug: Cetuximab
• Molecule Alteration: Missense mutation; p.S492R
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Standard-of-care sequencing assay
• Mechanism Description: K-RAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs).

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [11]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Cetuximab
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation.

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Non-small cell lung cancer [12]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-21 mainly achieves drug resistance by inhibiting cisplatin-induced apoptosis, and its specific mechanisms include the following: (1) improving the expression level of EGFR and protecting the toxic effect of tumor cells during chemotherapy; (2) Increase the expression of LRP and decrease the effective concentration of the target drug through the barrier of drug transport between nucleus and cell; (3) Enhance the expression of multidrug resistance associated protein (MRP1) and assist in pumping chemotherapeutic drugs from the inside to the outside of the cell.

Dacomitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [13]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Dacomitinib
• Molecule Alteration: IF-insertion; p.Y764_V765insHH (c.2292_2293insCATCAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Disease Class: Solid tumour/cancer [13]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Dacomitinib
• Molecule Alteration: Duplication; p.A767_V769 (c.2299_2307)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Disease Class: Solid tumour/cancer [13]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Dacomitinib
• Molecule Alteration: Duplication; p.S768_D770 (c.2302_2310)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [13]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Dacomitinib
• Molecule Alteration: Complex-indel; p.D770_770delinsGY (c.2308_2310delinsGGTTAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Disease Class: Lung adenocarcinoma [13]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Dacomitinib
• Molecule Alteration: Duplication; p.N771_H773 (c.2311_2319)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Disease Class: Lung adenocarcinoma [13]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Dacomitinib
• Molecule Alteration: IF-insertion; p.P772_H773insPNP (c.2317_2318insCTAACCCTC)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; SDS-PAGE assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay
• Mechanism Description: Mutation in the covalent binding site of either EGFR or HER2 is sufficient to lead to drug resistance.

Disease Class: Lung adenocarcinoma [14]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Dacomitinib
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Solid tumour/cancer [15]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Dacomitinib
• Molecule Alteration: Missense mutation; p.E709K (c.2125G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: myelomonocyti cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: macrophage-like cells; N.A.; .; N.A.
• In Vitro Model: IL3-dependent murine pro-B cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Balb/C mouse leukemia cells; Blood; Mus musculus (Mouse); CVCL_9099
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Disease Class: Solid tumour/cancer [15]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Dacomitinib
• Molecule Alteration: Complex-indel; p.E709_T710delinsD (c.2127_2129delAAC)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: myelomonocyti cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: macrophage-like cells; N.A.; .; N.A.
• In Vitro Model: IL3-dependent murine pro-B cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Balb/C mouse leukemia cells; Blood; Mus musculus (Mouse); CVCL_9099
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Disease Class: Lung adenocarcinoma [16]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Dacomitinib
• Molecule Alteration: Missense mutation; p.G719S (c.2155G>A)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [16]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Dacomitinib
• Molecule Alteration: Missense mutation; p.G719C (c.2155G>T)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [16]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Dacomitinib
• Molecule Alteration: Missense mutation; p.G719A (c.2156G>C)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Solid tumour/cancer [15]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Dacomitinib
• Molecule Alteration: Missense mutation; p.G719A (c.2156G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: myelomonocyti cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: macrophage-like cells; N.A.; .; N.A.
• In Vitro Model: IL3-dependent murine pro-B cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Balb/C mouse leukemia cells; Blood; Mus musculus (Mouse); CVCL_9099
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Disease Class: Lung adenocarcinoma [17]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Dacomitinib
• Molecule Alteration: IF-deletion; p.G729_D761 (c.2185_2283)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lung; .

Dasatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Dasatinib
• Molecule Alteration: Missense mutation; p.E711K
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Non-small cell lung cancer [19]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The transfection of miR 27b mimics led to downregulation of the expression levels of EGFR, whilst miR 27b inhibitors upregulated the expression levels of EGFR. Furthermore, it was demonstrated that the transfection of miR 27b mimics significantly suppressed the apoptosis and promote the viability of A549 human lung carcinoma cells. In line with this, the introduction of miR 27b inhibitors significantly induced apoptosis and inhibited the proliferation of A549 cells. These results indicate that miR 27b may promote NSCLC cell viability and enhance resistance to docetaxel treatment through direct inhibition of EGFR expression.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Prostate cancer [20]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA LOXL1-AS1/miR-let-7a-5p/EGFR-related pathway regulates the doxorubicin resistance of prostate cancer DU-145 cells.

Erlotinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [21], [22], [23]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Erlotinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Overall and disease-free assay
• Mechanism Description: Among patients with acquired resistance to EGFR TkIs, the presence of T790M defines a clinical subset with a relatively favorable prognosis and more indolent progression.

Disease Class: Non-small cell lung cancer [24], [25]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Erlotinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Computed tomography assay
• Mechanism Description: In addition, three (8%) patients acquired EGFR amplifications in their resistant specimens, all of which also acquired the classic T790M EGFR mutation. Moreover, in two cases with high-level EGFR amplification (>10-fold), it was clear by comparison of the peak heights on the SNaPshot chromatogram that the T790M allele was the amplified allele. They have identified several resistance mechanisms, two of which-EGFR mutation T790M and MET amplification have been validated in the clinic.

Disease Class: Non-small cell lung cancer [26]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Erlotinib
• Molecule Alteration: Missense mutation; p.C797S+p.T790M
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR/TKLS mediated apoptosis signaling pathway; Inhibition; hsa01521
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsy; ATP-binding pocket affinity comparison assay
• Mechanism Description: Several mechanisms of resistance have been described to EGFR-TkIs, such as the occurrence of secondary mutation (T790M, C797S), the activation of alternative signalling (Met, HGF, AXL, Hh, IGF-1R), the aberrance of the downstream pathways (AkT mutations, loss of PTEN), the impairment of the EGFR-TkIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism) and histological transformation.

Disease Class: EGFR-mutant non-small cell lung cancer [27]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: Erlotinib
• Molecule Alteration: Missense mutation; p.D761Y
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Low throughput experiment assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure.

Disease Class: EGFR-mutant non-small cell lung cancer [27]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: Erlotinib
• Molecule Alteration: Missense mutation; p.L747S
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Low throughput experiment assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure.

Disease Class: EGFR-mutant non-small cell lung cancer [27]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: Erlotinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Low throughput experiment assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure. At the point of acquired resistance, the T790M substitution may be accompanied by amplification of the EGFR gene as well.

Disease Class: Non-small cell lung cancer [28]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Erlotinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next generation sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall or disease-free survival assay
• Mechanism Description: One example is the acquisition of the T790M substitution in the membrane receptor EGFR conferring resistance to gefitinb and erlotinib in lung cancer in approximately 50% of patients.

Disease Class: Non-small cell lung cancer [29]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Erlotinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt signaling pathway; Activation; hsa04310
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: H2170 cells; Lung; Homo sapiens (Human); CVCL_1535
• Experiment for Molecule Alteration: Low throughput experiment assay
• Experiment for Drug Resistance: MTT cell viability assay
• Mechanism Description: H1975 cells are positive for the T790M EGFR mutation, which confers resistance to current EGFR TkI therapies.

Gefitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Non-small cell lung cancer [26]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.C797S
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK/MAPKsignaling pathway; Activation; hsa04210
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsy; ATP-binding pocket affinity comparison assay
• Mechanism Description: Known mechanisms are secondary resistance mutations occurring in the ATP-binding domain (such as T790M and C797S), mutation or amplification of bypass signallings (such as AXL, Hh, ERBb2, CRIPTO, etc), activating mutations in the downstream pathways (PI3k, AkT, MEk, RAF), low levels of mRNA or polymorphisms of the pro-apoptotic protein BIM, induction of a transcription programme for EMT and phenotypical changes, or induction of elevated tumour PD-L1 levels.

Disease Class: Non-small cell lung cancer [30], [31], [32]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK/MAPKsignaling pathway; Activation; hsa04210
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsy; ATP-binding pocket affinity comparison assay
• Mechanism Description: Known mechanisms are secondary resistance mutations occurring in the ATP-binding domain (such as T790M and C797S), mutation or amplification of bypass signallings (such as AXL, Hh, ERBb2, CRIPTO, etc), activating mutations in the downstream pathways (PI3k, AkT, MEk, RAF), low levels of mRNA or polymorphisms of the pro-apoptotic protein BIM, induction of a transcription programme for EMT and phenotypical changes, or induction of elevated tumour PD-L1 levels.

Disease Class: Lung adenocarcinoma [33], [34], [35]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Overall and disease-free assay
• Mechanism Description: A secondary T790M mutation of EGFR accounted for half the tumors with acquired resistance to gefitinib in Japanese patients. Other drug-resistant secondary mutations are uncommon in the EGFR gene.

Disease Class: Lung squamous cell carcinoma [36], [37], [38]

• Resistant Disease: Lung squamous cell carcinoma [ICD-11: 2C25.3]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Computed tomography (CT) scanning assay; Bone scintigraphy assay; Magnetic resonance imaging assay
• Mechanism Description: C-Met amplification, epithelial-mesenchymal transition, and kRAS and BRAF mutations were ruled out as alternative resistance mechanisms in the T790M-negative lung rebiopsy, suggesting that alternative oncogene aberrations such as HER2/Neu amplification, hepatocyte growth factor release by the tumor microenvironment, or other unidentified pathways contributed to the TkI resistance that was observed in the primary lesion.

Disease Class: EGFR-mutant non-small cell lung cancer [39]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: MGB SNP detection kit assay; Mutation Detection assay
• Experiment for Drug Resistance: Digital PCR assay
• Mechanism Description: Resistance mechanisms to EGFR-TkI therapy in EGFR-mutated NSCLC include secondary EGFR T790M mutation, c-Met amplification, PIk3CA mutation, and transformation to small-cell lung cancer.

Disease Class: Non-small cell lung cancer [26]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.C797S+p.T790M
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR/TKLS mediated apoptosis signaling pathway; Inhibition; hsa01521
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsy; ATP-binding pocket affinity comparison assay
• Mechanism Description: Several mechanisms of resistance have been described to EGFR-TkIs, such as the occurrence of secondary mutation (T790M, C797S), the activation of alternative signalling (Met, HGF, AXL, Hh, IGF-1R), the aberrance of the downstream pathways (AkT mutations, loss of PTEN), the impairment of the EGFR-TkIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism) and histological transformation.

Disease Class: Lung adenocarcinoma [40]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.D761Y
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct Sanger sequencing analysis
• Experiment for Drug Resistance: CellTiter-Blue cell viability assay
• Mechanism Description: The T790M mutation is common in patients with acquired resistance. The limited spectrum of TkI-resistant mutations in EGFR, which binds to erlotinib in the active conformation, contrasts with a wider range of second-site mutations seen with acquired resistance to imatinib, which binds to ABL and kIT, respectively, in closed conformations. Collectively, our data suggest that the type and nature of kinase inhibitor resistance mutations may be influenced by both anatomic site and mode of binding to the kinase target.

Disease Class: EGFR-mutant non-small cell lung cancer [27]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.L747S
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Low throughput experiment assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure.

Disease Class: EGFR-mutant non-small cell lung cancer [27]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.D761Y
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Low throughput experiment assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure.

Disease Class: EGFR-mutant non-small cell lung cancer [27]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Low throughput experiment assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure. At the point of acquired resistance, the T790M substitution may be accompanied by amplification of the EGFR gene as well.

Disease Class: Non-small cell lung cancer [28]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next generation sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall or disease-free survival assay
• Mechanism Description: One example is the acquisition of the T790M substitution in the membrane receptor EGFR conferring resistance to gefitinb and erlotinib in lung cancer in approximately 50% of patients.

Disease Class: Non-small cell lung cancer [33]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cos-7 cells; Lung; Homo sapiens (Human); CVCL_0224
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• Experiment for Molecule Alteration: qRT-PCR
• Mechanism Description: The DNA sequence of the EGFR gene in his tumor biopsy specimen at relapse revealed the presence of a second point mutation, resulting in threonine-to-methionine amino acid change at position 790 of EGFR. Structural modeling and biochemical studies showed that this second mutation led to gefitinib resistance.

Disease Class: Non-small cell lung cancer [33]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cos-7 cells; Lung; Homo sapiens (Human); CVCL_0224
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• Experiment for Molecule Alteration: qRT-PCR
• Mechanism Description: The DNA sequence of the EGFR gene in his tumor biopsy specimen at relapse revealed the presence of a second point mutation, resulting in threonine-to-methionine amino acid change at position 790 of EGFR. Structural modeling and biochemical studies showed that this second mutation led to gefitinib resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Non-small cell lung cancer [41]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Gefitinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vivo Model: Tumor xenograft in vivo model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Long Noncoding RNA LINC00460 promotes the gefitinib resistance of nonsmall cell lung cancer through EGFR by sponging miR-769-5p.

Disease Class: Non-small cell lung cancer [42]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Gefitinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 inhibit the protein level of EGFR and reverses gefitinib resistance in lung cancer cells.

Disease Class: Lung cancer [43]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Non-small cell lung cancer [26]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Sensitive Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.L858R
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK/MAPKsignaling pathway; Activation; hsa04210
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsy; ATP-binding pocket affinity comparison assay
• Mechanism Description: The two most common EGFR-activating mutations are small in-frame deletions in exon 19 (particularly E746-A750del) and amino acid substitution in exon 21 (leucine to arginine at codon 858 (L858R)), which collectively account for >90% of known activating EGFR mutations.2 3 These two alterations are the best-characterised mutations conferring sensitivity to EGFR-tyrosine kinase inhibitor (EGFR-TkI) therapy, resulting in higher response rates (RR) (up to 70%) and longer median survival (up to 24-30 months) than those observed in patients with wild-type (WT) EGFR. The higher sensitivity of these mutations relays in an increased affinity of the ATP-binding pocket for EGFR-TkIs as compared with WT EGFR.

Disease Class: Non-small cell lung cancer [26]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Sensitive Drug: Gefitinib
• Molecule Alteration: Frameshift mutation; p.E746-A750del
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK/MAPKsignaling pathway; Activation; hsa04210
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsy; ATP-binding pocket affinity comparison assay
• Mechanism Description: The two most common EGFR-activating mutations are small in-frame deletions in exon 19 (particularly E746-A750del) and amino acid substitution in exon 21 (leucine to arginine at codon 858 (L858R)), which collectively account for >90% of known activating EGFR mutations.2 3 These two alterations are the best-characterised mutations conferring sensitivity to EGFR-tyrosine kinase inhibitor (EGFR-TkI) therapy, resulting in higher response rates (RR) (up to 70%) and longer median survival (up to 24-30 months) than those observed in patients with wild-type (WT) EGFR. The higher sensitivity of these mutations relays in an increased affinity of the ATP-binding pocket for EGFR-TkIs as compared with WT EGFR.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Non-small cell lung cancer [44]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Sensitive Drug: Gefitinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: CCD-19Lu cells; Lung; Homo sapiens (Human); CVCL_2382
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: MRC-5 cells; Lung; Homo sapiens (Human); CVCL_0440
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: microRNA-200a directly targets and downregulates egfr and c-met to inhibit migration, invasion, and gefitinib resistance in non-small cell lung cancer.

Disease Class: Lung adenocarcinoma [45]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Gefitinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; EdU assay
• Mechanism Description: GAS5 was significantly downregulated in lung adenocarcinoma tissues compared with the paired adjacent non-tumorous tissue samples. Furthermore, lower GAS5 expression levels were associated with larger tumor sizes, poor tumor differentiation, and advanced pathological stages. However, GAS5 was almost equally expressed between benign tumors compared with the adjacent normal tissues. GAS5 was also overexpressed in EGFR-TkI sensitive cell lines compared with the resistant cell line. Using MTT, EdU incorporation, and colony formation assays, we showed that GAS5-expressing A549 cells displayed an elevated level of cell death. In addition to its pro-apoptotic effect in the A549 cell line, GAS5 overexpression also suppressed the growth of A549-derived tumors in nude mice treated with gefitinib. GAS5 overexpression was inversely correlated with the expression of the EGFR pathway and IGF-1R proteins.

Disease Class: Lung adenocarcinoma [46]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Gefitinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: RGFR signaling pathway; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: EGFR was negatively regulated by miR-7 mimic transfection, and downregulation of EGFR expression at the protein level largely correlated with elevated levels of miR-7 in the gefitinib-resistant cells. The results of the present study suggest that miR-7 may have central roles in the development of resistance to endocrine therapy in resistant cells through regulating the expression of EGFR in cancer cells.

Disease Class: Non-small cell lung cancer [47]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Sensitive Drug: Gefitinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-133b suppresses the expression of EGFR, miR-133b transfection may modulate apoptosis, invasion and sensitivity to EGFR-TkI through the EGFR signaling pathways.

Icotinib hydrochloride

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Non-small cell lung cancer [4], [5], [6]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Icotinib hydrochloride
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Directional sequencing assay; Direct sequencing assay
• Experiment for Drug Resistance: Progression-free and post-progression survival asaay
• Mechanism Description: The identification of T790M as acquired resistance mechanism was clinically feasible. Although T790M had no prognostic or predictive role in the present study, further research is necessary to identify patients with T790M-mutant tumors who might benefit from newly developed T790M-specific TkIs.

Imatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.E711K
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Lapatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.V292E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.R705G
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.L760F
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.K284E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.I706T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.G696E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.A822V
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.V292M
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.P741S
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.G288D
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Lapatinib
• Molecule Alteration: Missense mutation; p.E711K
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Nilotinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Nilotinib
• Molecule Alteration: Missense mutation; p.E711K
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Olmutinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [48]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Olmutinib
• Molecule Alteration: Missense mutation; p.C797S
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Computed tomography assay; Progression-free survival assay
• Mechanism Description: A recent preclinical study reported that EGFR C797S, L718Q, and L844V mutations cause resistance to both WZ4002 and CO-1686 but only EGFR C797S leads to AZD9291 resistance, suggesting that C797S can serve as acquired resistance to irreversible pyrimidine-based EGFR inhibitors given the similar chemical structure of third-generation EGFR TkIs.

Osimertinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Non-small cell lung cancer [49]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Osimertinib
• Molecule Alteration: Missense mutation; p.C797S
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Cell-free plasma DNA assay; Next generation assay; Droplet digital PCR assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Acquired EGFR C797S mediates resistance to AZD9291 in advanced non-small cell lung cancer harboring EGFR T790M.

Disease Class: Non-small cell lung cancer [50]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Osimertinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Sanger sequencing assay; Fluorescence in situ hybridization assay; Real-time polymerase chain reaction assay; Targeted exome sequencing assay
• Experiment for Drug Resistance: Computed tomography assay
• Mechanism Description: Acquired resistance mechanisms of AZD9291 in patients with EGFRT790M-mutant NSCLC who failed treatment with first-generation EGFR TkIs include the loss of EGFRT790M-mutant clones plus alternative pathway activation or histologic transformation and EGFR ligand-dependent activation.

Paclitaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Non-small cell lung cancer [51]

• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: 95D cells; Lung; Homo sapiens (Human); CVCL_7110
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-7 sensitizes NSCLC cells to PTX and inhibites EGFR expression in A549 cells.

Panitumumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Colorectal cancer [9]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Panitumumab
• Molecule Alteration: Missense mutation; p.G465E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Colon cells; Colon; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Liquid biopsy assay
• Mechanism Description: Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Disease Class: Metastatic colorectal cancer [10]

• Resistant Disease: Metastatic colorectal cancer [ICD-11: 2D85.0]
• Resistant Drug: Panitumumab
• Molecule Alteration: Missense mutation; p.S492R
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Standard-of-care sequencing assay
• Mechanism Description: K-RAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs).

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Metastatic colorectal cancer [52]

• Resistant Disease: Metastatic colorectal cancer [ICD-11: 2D85.0]
• Resistant Drug: Panitumumab
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: EGFR signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: ERBB2/MET/IGF-1R signalling pathway; Activation; hsa04520
• Cell Pathway Regulation: RAF/KRAS/MEK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• Experiment for Drug Resistance: Progression-free survival (PFS) analysis; Overall survival (OS) analysis
• Mechanism Description: Cetuximab and panitumumab are monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) that are effective agents for metastatic colorectal cancer (mCRC). The mechanisms of resistance refer to intrinsic and extrinsic alterations of tumours. The intrinsic mechanisms include EGFR ligand overexpression, EGFR alteration, RAS/RAF/PI3K gene mutations, ERBB2/MET/IGF-1R activation, metabolic remodelling, microsatellite instability and autophagy. Extrinsic alterations mainly disrupt the tumour microenvironment, specifically immune cells, cancer-associated fibroblasts (CAFs) and angiogenesis.

Pemetrexed

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Non-small cell lung cancer [39]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Pemetrexed
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: MGB SNP detection kit assay; Mutation Detection assay
• Experiment for Drug Resistance: Digital PCR assay
• Mechanism Description: Resistance mechanisms to EGFR-TkI therapy in EGFR-mutated NSCLC include secondary EGFR T790M mutation, c-Met amplification, PIk3CA mutation, and transformation to small-cell lung cancer.

Pertuzumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.V292E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.R705G
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.L760F
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.K284E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.I706T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.G696E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.A822V
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.V292M
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.P741S
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.G288D
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Pertuzumab
• Molecule Alteration: Missense mutation; p.E711K
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Temozolomide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioblastoma multiforme [53]

• Sensitive Disease: Glioblastoma multiforme [ICD-11: 2A00.03]
• Sensitive Drug: Temozolomide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR181b modulates chemosensitivity of glioblastoma multiforme cells to temozolomide by targeting the epidermal growth factor receptor.

Trastuzumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.V292E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.I706T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.R705G
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.L760F
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.K284E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.G696E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.A822V
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.V292M
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.P741S
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.G288D
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab
• Molecule Alteration: Missense mutation; p.E711K
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [54]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Trastuzumab
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colcount colony counter assay
• Mechanism Description: miR-7 suppression of HER2deta16 oncogenic activity is mediated through inactivation of Src kinase and suppression of EGFR expression implies that targeting these pathways would also suppress HER2deta16 tumorigenesis. HER2deta16 suppresses expression of the miR-7 tumor suppressor and reestablished miR-7 expression significantly inhibits HER2deta16 mediated tumor cell proliferation and migration and miR-7 sensitizes HER2deta16 expressing cells to trastuzumab treatment.

Trastuzumab emtansine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.V292E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.R705G
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.L760F
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.K284E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.I706T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.G696E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.A822V
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.V292M
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.P741S
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Disease Class: HER2 positive breast cancer [18]

• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Resistant Drug: Trastuzumab emtansine
• Molecule Alteration: Missense mutation; p.G288D
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

Vandetanib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [55]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Vandetanib
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: Calu-6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.L858R (c.2573T>G) in gene EGFR cause the sensitivity of Vandetanib by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [56]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Vandetanib
• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: PC-14 cells; Lung; Homo sapiens (Human); CVCL_1640
• In Vitro Model: WiDR cells; Colon; Homo sapiens (Human); CVCL_2760
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The if-deletion p.E746_A750delELREA (c.2236_2250del15) in gene EGFR cause the sensitivity of Vandetanib by unusual activation of pro-survival pathway.

Vemurafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [57]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Vemurafenib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/PI3K/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Mel-CV cells; Skin; Homo sapiens (Human); CVCL_S996
• Experiment for Molecule Alteration: Immunohistochemical staining assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-7 expression was decreased in both VemR A375 and Mel-CVR melanoma cells and its low expression contributed to BRAFi resistance. Furthermore, by decreasing the expression levels of EGFR, IGF-1R and CRAF, miR-7 could inhibit the activation of RAS/RAF/MEk/ERk (MAPk) and PI3k/AkT pathway and partially reverse the resistance to BRAFi in VemR A375 melanoma cells.

Patented Agent(s) 1 drug(s) in total

Abivertinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [58]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Abivertinib
• Molecule Alteration: Missense mutation; p.T790M (c.2369C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: BEAS-2B cells; Bronchus; Homo sapiens (Human); CVCL_0168
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: HT1080 cells; Acetabulum; Homo sapiens (Human); CVCL_0317
• In Vivo Model: Nu/Nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: WST-1 assay

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [58]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Abivertinib
• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: BEAS-2B cells; Bronchus; Homo sapiens (Human); CVCL_0168
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: HT1080 cells; Acetabulum; Homo sapiens (Human); CVCL_0317
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis; ELISA assay
• Experiment for Drug Resistance: WST-1 assay

Clinical Trial Drug(s) 10 drug(s) in total

Nazartinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Lung adenocarcinoma [59]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Nazartinib
• Molecule Alteration: Duplication; p.N771_H773 (c.2311_2319)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: HaCaT cells; Tongue; Homo sapiens (Human); CVCL_0038
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor

Disease Class: Solid tumour/cancer [59]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Nazartinib
• Molecule Alteration: Duplication; p.S768_D770 (c.2302_2310)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: HaCaT cells; Tongue; Homo sapiens (Human); CVCL_0038
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor

Disease Class: Solid tumour/cancer [59]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Nazartinib
• Molecule Alteration: Duplication; p.N771_H773 (c.2311_2319)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: HaCaT cells; Tongue; Homo sapiens (Human); CVCL_0038
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor

Selumetinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [60]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Selumetinib
• Molecule Alteration: Missense mutation; p.T790M (c.2369C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vivo Model: BALB/C nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay

AUY922

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Solid tumour/cancer [61]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.A763_Y764insFQEA (c.2290_2291insTTCAAGAGGCAT)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. The non-geldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis.

Disease Class: Solid tumour/cancer [61]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.Y764_V765insHH (c.2292_2293insCATCAT)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. The non-geldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis.

Disease Class: Solid tumour/cancer [61]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: AUY922
• Molecule Alteration: Duplication; p.S768_D770 (c.2302_2310)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. The non-geldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis.

Disease Class: Solid tumour/cancer [61]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.P772_H773insGNP (c.2316_2317insGGTAACCCT)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. The non-geldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis.

Disease Class: Solid tumour/cancer [61]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: AUY922
• Molecule Alteration: Duplication; p.H773 (c.2317_2319)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. The non-geldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [61]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.A763_Y764insFQEA (c.2290_2291insTTCAAGAGGCAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: NCI-H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: BID007 cells; Pleural effusion; Homo sapiens (Human); CVCL_W890
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter Glo assay; IC50 assay

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: Duplication; p.A767_V769 (c.2299_2307)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: Duplication; p.S768_D770 (c.2302_2310)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.A767_V769dupASV (c.2308_2309insCAAGCGTAG)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: Duplication; p.D770_P772 (c.2308_2316)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.D770_N771insGV (c.2310_2311insGGTGTA)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.D770_N771insGF (c.2310_2311insGGTTTT)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.S768_D770dupSVD (c.2311_2312insGCGTAGACA)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: Duplication; p.P772_H773 (c.2314_2319)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.P772_H773insYNP (c.2315_2316insTTATAACCC)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: Duplication; p.H773 (c.2317_2319)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.H773_V774insAH (c.2320_2321insCACATG)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.A763_Y764insFQEA
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.A767_V774ins
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.V769_D770insASV
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.A770_N771insNPY
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AUY922
• Molecule Alteration: IF-insertion; p.D770_N771insSVD
• Experimental Note: Identified from the Human Clinical Data

Naquotinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Solid tumour/cancer [63]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Naquotinib
• Molecule Alteration: IF-insertion; p.Y764_V765insHH (c.2292_2293insCATCAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9ER cells; N.A.; .; N.A.
• In Vitro Model: BID007 cells; Pleural effusion; Homo sapiens (Human); CVCL_W890
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: There is a mechanism for resistance associated with EGFR Y764_V765insHH mutation, one of the most resistant mutations. We demonstrated that in Y764_V765insHH, histidine residues inserted in the Val765 and Met766 positions upregulated the EGFR kinase activity and caused steric insensitivity to the particular EGFR-TKIs.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Solid tumour/cancer [63]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Naquotinib
• Molecule Alteration: Complex-indel; p.L747_P753delinsS (c.2240_2257del18)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9ER cells; N.A.; .; N.A.
• In Vitro Model: BID007 cells; Pleural effusion; Homo sapiens (Human); CVCL_W890
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: There is a mechanism for resistance associated with EGFR Y764_V765insHH mutation, one of the most resistant mutations. We demonstrated that in Y764_V765insHH, histidine residues inserted in the Val765 and Met766 positions upregulated the EGFR kinase activity and caused steric insensitivity to the particular EGFR-TKIs.

Disease Class: Solid tumour/cancer [63]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Naquotinib
• Molecule Alteration: IF-insertion; p.A763_Y764insFQEA (c.2290_2291insTTCAAGAGGCAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9ER cells; N.A.; .; N.A.
• In Vitro Model: BID007 cells; Pleural effusion; Homo sapiens (Human); CVCL_W890
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: There is a mechanism for resistance associated with EGFR Y764_V765insHH mutation, one of the most resistant mutations. We demonstrated that in Y764_V765insHH, histidine residues inserted in the Val765 and Met766 positions upregulated the EGFR kinase activity and caused steric insensitivity to the particular EGFR-TKIs.

Disease Class: Solid tumour/cancer [63]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Naquotinib
• Molecule Alteration: Duplication; p.A767_V769 (c.2299_2307)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9ER cells; N.A.; .; N.A.
• In Vitro Model: BID007 cells; Pleural effusion; Homo sapiens (Human); CVCL_W890
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: There is a mechanism for resistance associated with EGFR Y764_V765insHH mutation, one of the most resistant mutations. We demonstrated that in Y764_V765insHH, histidine residues inserted in the Val765 and Met766 positions upregulated the EGFR kinase activity and caused steric insensitivity to the particular EGFR-TKIs.

Disease Class: Solid tumour/cancer [63]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Naquotinib
• Molecule Alteration: IF-insertion; p.P772_H773insGNP (c.2316_2317insGGTAACCCT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9ER cells; N.A.; .; N.A.
• In Vitro Model: BID007 cells; Pleural effusion; Homo sapiens (Human); CVCL_W890
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: There is a mechanism for resistance associated with EGFR Y764_V765insHH mutation, one of the most resistant mutations. We demonstrated that in Y764_V765insHH, histidine residues inserted in the Val765 and Met766 positions upregulated the EGFR kinase activity and caused steric insensitivity to the particular EGFR-TKIs.

Disease Class: Solid tumour/cancer [63]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Naquotinib
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9ER cells; N.A.; .; N.A.
• In Vitro Model: BID007 cells; Pleural effusion; Homo sapiens (Human); CVCL_W890
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: There is a mechanism for resistance associated with EGFR Y764_V765insHH mutation, one of the most resistant mutations. We demonstrated that in Y764_V765insHH, histidine residues inserted in the Val765 and Met766 positions upregulated the EGFR kinase activity and caused steric insensitivity to the particular EGFR-TKIs.

Disease Class: Lung adenocarcinoma [63]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Naquotinib
• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9ER cells; N.A.; .; N.A.
• In Vitro Model: BID007 cells; Pleural effusion; Homo sapiens (Human); CVCL_W890
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: There is a mechanism for resistance associated with EGFR Y764_V765insHH mutation, one of the most resistant mutations. We demonstrated that in Y764_V765insHH, histidine residues inserted in the Val765 and Met766 positions upregulated the EGFR kinase activity and caused steric insensitivity to the particular EGFR-TKIs.

Disease Class: Lung adenocarcinoma [63]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Naquotinib
• Molecule Alteration: IF-insertion; p.A763_Y764insFQEA (c.2290_2291insTTCAAGAGGCAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9ER cells; N.A.; .; N.A.
• In Vitro Model: BID007 cells; Pleural effusion; Homo sapiens (Human); CVCL_W890
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: There is a mechanism for resistance associated with EGFR Y764_V765insHH mutation, one of the most resistant mutations. We demonstrated that in Y764_V765insHH, histidine residues inserted in the Val765 and Met766 positions upregulated the EGFR kinase activity and caused steric insensitivity to the particular EGFR-TKIs.

Disease Class: Lung adenocarcinoma [63]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Naquotinib
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9ER cells; N.A.; .; N.A.
• In Vitro Model: BID007 cells; Pleural effusion; Homo sapiens (Human); CVCL_W890
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: There is a mechanism for resistance associated with EGFR Y764_V765insHH mutation, one of the most resistant mutations. We demonstrated that in Y764_V765insHH, histidine residues inserted in the Val765 and Met766 positions upregulated the EGFR kinase activity and caused steric insensitivity to the particular EGFR-TKIs.

Poziotinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [64]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Poziotinib
• Molecule Alteration: IF-insertion; p.A763_Y764insFQEA (c.2290_2291insTTCAAGAGGCAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The if-insertion p.A763_Y764insFQEA (c.2290_2291insTTCAAGAGGCAT) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Solid tumour/cancer [64]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Poziotinib
• Molecule Alteration: Duplication; p.A767_V769 (c.2299_2307)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The duplication p.A767_V769 (c.2299_2307) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Solid tumour/cancer [64]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Poziotinib
• Molecule Alteration: Duplication; p.S768_D770 (c.2302_2310)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The duplication p.S768_D770 (c.2302_2310) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Solid tumour/cancer [64]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Poziotinib
• Molecule Alteration: Duplication; p.N771_H773 (c.2311_2319)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The duplication p.N771_H773 (c.2311_2319) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Solid tumour/cancer [64]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Poziotinib
• Molecule Alteration: IF-insertion; p.P772_H773insGNP (c.2316_2317insGGTAACCCT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The if-insertion p.P772_H773insGNP (c.2316_2317insGGTAACCCT) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Lung adenocarcinoma [64]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Poziotinib
• Molecule Alteration: Duplication; p.A767_V769 (c.2299_2307)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The duplication p.A767_V769 (c.2299_2307) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Lung adenocarcinoma [64]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Poziotinib
• Molecule Alteration: Complex-indel; p.N771_771delinsFH (c.2311_2313delinsTTTCAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The complex-indel p.N771_771delinsFH (c.2311_2313delinsTTTCAT) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Lung adenocarcinoma [64]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Poziotinib
• Molecule Alteration: IF-insertion; p.P772_H773insGNP (c.2316_2317insGGTAACCCT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The if-insertion p.P772_H773insGNP (c.2316_2317insGGTAACCCT) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Lung adenocarcinoma [64]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Poziotinib
• Molecule Alteration: Duplication; p.A767_V769 (c.2299_2307)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The duplication p.A767_V769 (c.2299_2307) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Lung adenocarcinoma [64]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Poziotinib
• Molecule Alteration: Duplication; p.S768_D770 (c.2302_2310)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The duplication p.S768_D770 (c.2302_2310) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Lung adenocarcinoma [64]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Poziotinib
• Molecule Alteration: Complex-indel; p.D770_770delinsGY (c.2308_2310delinsGGTTAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The complex-indel p.D770_770delinsGY (c.2308_2310delinsGGTTAT) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Lung adenocarcinoma [64]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Poziotinib
• Molecule Alteration: Duplication; p.D770_P772 (c.2308_2316)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The duplication p.D770_P772 (c.2308_2316) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Lung adenocarcinoma [64]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Poziotinib
• Molecule Alteration: IF-insertion; p.D770_N771insG (c.2310_2311insGGT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The if-insertion p.D770_N771insG (c.2310_2311insGGT) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Lung adenocarcinoma [64]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Poziotinib
• Molecule Alteration: Duplication; p.N771_H773 (c.2311_2319)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The duplication p.N771_H773 (c.2311_2319) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target.

Disease Class: Lung adenocarcinoma [64]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Poziotinib
• Molecule Alteration: Missense mutation; p.S768I (c.2303G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: CUTO14 cells; N.A.; .; N.A.
• In Vivo Model: Female nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay
• Mechanism Description: The missense mutation p.S768I (c.2303G>T) in gene EGFR cause the sensitivity of Poziotinib by aberration of the drug's therapeutic target

Tesevatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [65]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Tesevatinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Computed tomography assay
• Mechanism Description: The most common mechanism of acquired resistance is caused by the development of the T790M mutation in exon 20 of EGFR in nearly 50% of patients, whereas 10% of the patients have amplification of the oncogene MET as a means of resistance.

AEE-788

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [66]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: AEE-788
• Molecule Alteration: Missense mutation; p.N826S (c.2477A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter96 Proliferation assay
• Mechanism Description: The missense mutation p.N826S (c.2477A>G) in gene EGFR cause the resistance of AEE-788 by aberration of the drug's therapeutic target

Disease Class: Lung adenocarcinoma [67]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: AEE-788
• Molecule Alteration: Missense mutation; p.T790M (c.2369C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Enzyme kinetic assays
• Mechanism Description: The missense mutation p.T790M (c.2369C>T) in gene EGFR cause the resistance of AEE-788 by aberration of the drug's therapeutic target

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [66]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: AEE-788
• Molecule Alteration: Complex-indel; p.L747_P753delinsS (c.2240_2257del18)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter96 Proliferation assay
• Mechanism Description: The complex-indel p.L747_P753delinsS (c.2240_2257del18) in gene EGFR cause the sensitivity of AEE-788 by aberration of the drug's therapeutic target.

Disease Class: Solid tumour/cancer [66]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: AEE-788
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter96 Proliferation assay
• Mechanism Description: The missense mutation p.L858R (c.2573T>G) in gene EGFR cause the sensitivity of AEE-788 by aberration of the drug's therapeutic target

Lifirafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [68]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Lifirafenib
• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vitro Model: WiDR cells; Colon; Homo sapiens (Human); CVCL_2760
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vivo Model: Female NOD/SCID and BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Tumor volume measurement assay

Disease Class: Solid tumour/cancer [68]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Lifirafenib
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vitro Model: WiDR cells; Colon; Homo sapiens (Human); CVCL_2760
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vivo Model: Female NOD/SCID and BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Tumor volume measurement assay

CUDC-101

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [69]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: CUDC-101
• Molecule Alteration: Missense mutation; p.T790M (c.2369C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Female athymic mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Perkin-Elmer ATPlite assay
• Mechanism Description: The missense mutation p.T790M (c.2369C>T) in gene EGFR cause the sensitivity of CUDC-101 by aberration of the drug's therapeutic target

Lazertinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [70]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Lazertinib
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9GR cells; Lung; Homo sapiens (Human); CVCL_V337
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: H2291 cells; Lung; Homo sapiens (Human); CVCL_1546
• In Vivo Model: Female BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: Cell-free kinase assay; IC50 assay

Disease Class: Lung adenocarcinoma [70]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Lazertinib
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9GR cells; Lung; Homo sapiens (Human); CVCL_V337
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: H2291 cells; Lung; Homo sapiens (Human); CVCL_1546
• In Vivo Model: Female BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: Cell-free kinase assay; IC50 assay

Disease Class: Lung adenocarcinoma [70]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Lazertinib
• Molecule Alteration: Missense mutation; p.L861Q (c.2582T>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9GR cells; Lung; Homo sapiens (Human); CVCL_V337
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: H2291 cells; Lung; Homo sapiens (Human); CVCL_1546
• In Vivo Model: Female BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: Cell-free kinase assay; IC50 assay

Discontinued Drug(s) 2 drug(s) in total

Rociletinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Non-small cell lung cancer [39], [71], [72]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Rociletinib
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Blood-based tumor genotyping assay; Liquid Biopsies assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Overall and disease-free assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

Disease Class: Non-small cell lung cancer [71], [72]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Rociletinib
• Molecule Alteration: Missense mutation; p.L798I
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Blood-based tumor genotyping assay; Liquid Biopsies assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Overall and disease-free assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

Disease Class: Non-small cell lung cancer [71], [72]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Rociletinib
• Molecule Alteration: Missense mutation; p.C797S
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Blood-based tumor genotyping assay; Liquid Biopsies assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Overall and disease-free assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

S-1

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: EGFR-mutant non-small cell lung cancer [39]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: S-1
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: MGB SNP detection kit assay; Mutation Detection assay
• Experiment for Drug Resistance: Digital PCR assay
• Mechanism Description: Resistance mechanisms to EGFR-TkI therapy in EGFR-mutated NSCLC include secondary EGFR T790M mutation, c-Met amplification, PIk3CA mutation, and transformation to small-cell lung cancer.

Preclinical Drug(s) 16 drug(s) in total

AV-412

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [73]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: AV-412
• Molecule Alteration: Missense mutation; p.T790M (c.2369C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: A4 cells; N.A.; Mus musculus (Mouse); CVCL_F962
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: 3H-thymidine incorporation assay
• Mechanism Description: The missense mutation p.T790M (c.2369C>T) in gene EGFR cause the sensitivity of AV-412 by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [73]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: AV-412
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: A4 cells; N.A.; Mus musculus (Mouse); CVCL_F962
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: 3H-thymidine incorporation assay
• Mechanism Description: The missense mutation p.L858R (c.2573T>G) in gene EGFR cause the sensitivity of AV-412 by aberration of the drug's therapeutic target

AZD-3759

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [74]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: AZD-3759
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H838 cells; Lung; Homo sapiens (Human); CVCL_1594
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NCI-H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Enzyme-linked immunosorbent assay
• Mechanism Description: AZD3759, a selective EGFR inhibitor that can fully penetrate the blood-brain barrier (BBB), with equal free concentrations in the blood, cerebrospinal fluid, and brain tissue. Treatment with AZD3759 causes tumor regression in subcutaneous xenograft, leptomeningeal metastasis (LM), and brain metastasis (BM) lung cancer models and prevents the development of BM in nude mice.

Buparlisib/Osimertinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [75]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Buparlisib/Osimertinib
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Axon guidance signaling pathway; Inhibition; hsa04360
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC4006 cells; Lung; Homo sapiens (Human); CVCL_1269
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NCI-H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: 11-18 cells; Lung; Homo sapiens (Human); CVCL_6659
• In Vivo Model: Athymic female mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and mitogen-activated protein kinase (MAPK) pathway signaling under continuous EGFR inhibition in osimertinib sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member YES1 was amplified in osimertinib- resistant EGFR-mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors.

EAI045

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [76]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: EAI045
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HaCaT cells; Tongue; Homo sapiens (Human); CVCL_0038
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Drug Resistance: CellTitre-Glo assay; MTS assay
• Mechanism Description: EAI045 is a kind of EGFR tyrosine kinase inhibitor.

EKI-285

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [77]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: EKI-285
• Molecule Alteration: Missense mutation; p.H773L (c.2318A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NIH-H1975; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.H773L (c.2318A>T) in gene EGFR cause the resistance of EKI-285 by aberration of the drug's therapeutic target

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [40]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: EKI-285
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lung adenocarcinomas tissue; .
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.L858R (c.2573T>G) in gene EGFR cause the sensitivity of EKI-285 by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [78]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: EKI-285
• Molecule Alteration: Missense mutation; p.L844V (c.2530C>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: HCC827EP cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: H3255DR cells; Lung; Homo sapiens (Human); CVCL_DI56
• In Vitro Model: H197 cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay; CytoSelect 96-well cell transformation assay

Disease Class: Solid tumour/cancer [78]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: EKI-285
• Molecule Alteration: Missense mutation; p.L718Q (c.2153T>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: HCC827EP cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: H3255DR cells; Lung; Homo sapiens (Human); CVCL_DI56
• In Vitro Model: H197 cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay; CytoSelect 96-well cell transformation assay

ER2

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [79]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: ER2
• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC9GR cells; Lung; Homo sapiens (Human); CVCL_V337
• In Vitro Model: H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: H322 cells; Lung; Homo sapiens (Human); CVCL_1556
• In Vivo Model: Female athymic BALB-c/nu mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: FACS assay; Propidium iodide staining assay
• Mechanism Description: ER2 suppressed EGFR pathway and induced G1 arrest and apoptosis in NSCLC cells. ER2 inhibited EGF-stimulated VEGF production. ER2 induced anti-tumor activity in combination with cisplatin in xenograft models.

Erlotinib/Ganetespib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [80]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Erlotinib/Ganetespib
• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NCI-H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: NCI-HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: NCI-H322 cells; Lung; Homo sapiens (Human); CVCL_1556
• In Vitro Model: NCI-H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vivo Model: NSCLC xenograft tumor model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer Glo assay

hEGFR vIII-CD3 bi-scFv

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Brain glioma [81]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Sensitive Drug: hEGFR vIII-CD3 bi-scFv
• Molecule Alteration: Complex-indel; (c.89_889del11867)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Drug Resistance: Chromium release assay; FACS assay

JBJ-04-125-02

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [82]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: JBJ-04-125-02
• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Experimental Note: Identified from the Human Clinical Data

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [82]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: JBJ-04-125-02
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vivo Model: Genetically engineered mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: MTS assay

MM-151

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [83]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: MM-151
• Molecule Alteration: Missense mutation; p.S492R (c.1476C>G)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. Upon MM-151 treatment, EGFR ECD mutations decline in circulating cell-free tumor DNA (ctDNA) of CRC patients who previously developed resistance to EGFR blockade.

Disease Class: Colorectal cancer [83]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: MM-151
• Molecule Alteration: Missense mutation; p.R451C (c.1351C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. Upon MM-151 treatment, EGFR ECD mutations decline in circulating cell-free tumor DNA (ctDNA) of CRC patients who previously developed resistance to EGFR blockade.

Disease Class: Colorectal cancer [83]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: MM-151
• Molecule Alteration: Missense mutation; p.S464L (c.1391C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. Upon MM-151 treatment, EGFR ECD mutations decline in circulating cell-free tumor DNA (ctDNA) of CRC patients who previously developed resistance to EGFR blockade.

Disease Class: Colorectal cancer [83]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: MM-151
• Molecule Alteration: Missense mutation; p.G465R (c.1393G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. Upon MM-151 treatment, EGFR ECD mutations decline in circulating cell-free tumor DNA (ctDNA) of CRC patients who previously developed resistance to EGFR blockade.

Disease Class: Colorectal cancer [83]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: MM-151
• Molecule Alteration: Missense mutation; p.G465E (c.1394G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. Upon MM-151 treatment, EGFR ECD mutations decline in circulating cell-free tumor DNA (ctDNA) of CRC patients who previously developed resistance to EGFR blockade.

Disease Class: Colorectal cancer [83]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: MM-151
• Molecule Alteration: Missense mutation; p.K467T (c.1400A>C)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. Upon MM-151 treatment, EGFR ECD mutations decline in circulating cell-free tumor DNA (ctDNA) of CRC patients who previously developed resistance to EGFR blockade.

Disease Class: Colorectal cancer [83]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: MM-151
• Molecule Alteration: Missense mutation; p.I491M (c.1473A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. Upon MM-151 treatment, EGFR ECD mutations decline in circulating cell-free tumor DNA (ctDNA) of CRC patients who previously developed resistance to EGFR blockade.

Necitumumab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [84]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Necitumumab
• Molecule Alteration: Missense mutation; p.S492R (c.1476C>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: LK2 cells; Ascites; Homo sapiens (Human); CVCL_W132
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: FACS assay

OBX1-012

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Solid tumour/cancer [85]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: OBX1-012
• Molecule Alteration: IF-insertion; p.P772_H773insGNP (c.2316_2317insGGTAACCCT)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: OBX1-012 treatment was highly effective against human EGFR-mutant lung cancer models with or without EGFR T790M, not only in vitro but also in vivo. However, OBX1-012 like other EGFR-TKIs failed to exhibit efficacy for the exon 20 insertion mutation or C797S mutation, which was generated by site-directed mutagenesis and stable transfection of Ba/F3 cells.

Osimertinib/Selumetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [75]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Osimertinib/Selumetinib
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Axon guidance signaling pathway; Inhibition; hsa04360
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC4006 cells; Lung; Homo sapiens (Human); CVCL_1269
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NCI-H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: 11-18 cells; Lung; Homo sapiens (Human); CVCL_6659
• In Vivo Model: Athymic female mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and mitogen-activated protein kinase (MAPK) pathway signaling under continuous EGFR inhibition in osimertinib sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member YES1 was amplified in osimertinib- resistant EGFR-mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors.

Disease Class: Lung adenocarcinoma [86]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Osimertinib/Selumetinib
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: SYTOX green cucleic acid stain assay

TAE226

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [87]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: TAE226
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NCI-H2228 cells; Lung; Homo sapiens (Human); CVCL_1543
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H838 cells; Lung; Homo sapiens (Human); CVCL_1594
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC4006 cells; Lung; Homo sapiens (Human); CVCL_1269
• In Vitro Model: NCI-H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: NCI-H820 cells; Lymph node; Homo sapiens (Human); CVCL_1592
• In Vitro Model: NCI-H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: NCI-H1993 cells; Lymph node; Homo sapiens (Human); CVCL_1512
• In Vitro Model: NCI-H1819 cells; Lymph node; Homo sapiens (Human); CVCL_1497
• In Vitro Model: NCI-H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: NCI-H1648 cells; Lymph node; Homo sapiens (Human); CVCL_1482
• In Vitro Model: NCI-H1299 cells; Lymph node; Homo sapiens (Human); CVCL_0060
• In Vitro Model: MKN45 cells; Liver; Homo sapiens (Human); CVCL_0434
• In Vivo Model: BALB/c-nu/nu female nude mouse PC9 xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Disease Class: Lung adenocarcinoma [87]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: TAE226
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NCI-H2228 cells; Lung; Homo sapiens (Human); CVCL_1543
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H838 cells; Lung; Homo sapiens (Human); CVCL_1594
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC4006 cells; Lung; Homo sapiens (Human); CVCL_1269
• In Vitro Model: NCI-H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: NCI-H820 cells; Lymph node; Homo sapiens (Human); CVCL_1592
• In Vitro Model: NCI-H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• In Vitro Model: NCI-H1993 cells; Lymph node; Homo sapiens (Human); CVCL_1512
• In Vitro Model: NCI-H1819 cells; Lymph node; Homo sapiens (Human); CVCL_1497
• In Vitro Model: NCI-H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: NCI-H1648 cells; Lymph node; Homo sapiens (Human); CVCL_1482
• In Vitro Model: NCI-H1299 cells; Lymph node; Homo sapiens (Human); CVCL_0060
• In Vitro Model: MKN45 cells; Liver; Homo sapiens (Human); CVCL_0434
• In Vivo Model: BALB/c-nu/nu female nude mouse PC9 xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

TAS6417

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [88]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: TAS6417
• Molecule Alteration: IF-insertion; p.A763_Y764insFQEA (c.2290_2291insTTCAAGAGGCAT)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: NCI-H1875 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: LXF 2378L cells; N.A.; .; N.A.
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.

Disease Class: Solid tumour/cancer [88]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: TAS6417
• Molecule Alteration: Duplication; p.A767_V769 (c.2299_2307)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: NCI-H1875 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: LXF 2378L cells; N.A.; .; N.A.
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.

Disease Class: Solid tumour/cancer [88]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: TAS6417
• Molecule Alteration: Duplication; p.S768_D770 (c.2302_2310)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: NCI-H1875 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: LXF 2378L cells; N.A.; .; N.A.
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.

Disease Class: Solid tumour/cancer [88]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: TAS6417
• Molecule Alteration: IF-insertion; p.D770_N771insG (c.2310_2311insGGT)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: NCI-H1875 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: LXF 2378L cells; N.A.; .; N.A.
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.

Disease Class: Solid tumour/cancer [88]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: TAS6417
• Molecule Alteration: Duplication; p.N771_H773 (c.2311_2319)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: NCI-H1875 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: LXF 2378L cells; N.A.; .; N.A.
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.

Disease Class: Solid tumour/cancer [88]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: TAS6417
• Molecule Alteration: Duplication; p.P772_H773 (c.2314_2319)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: NCI-H1875 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: LXF 2378L cells; N.A.; .; N.A.
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.

Disease Class: Lung adenocarcinoma [88]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: TAS6417
• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: NCI-H1875 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: LXF 2378L cells; N.A.; .; N.A.
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.

Disease Class: Lung adenocarcinoma [88]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: TAS6417
• Molecule Alteration: Duplication; p.A767_V769 (c.2299_2307)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: NCI-H1875 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: LXF 2378L cells; N.A.; .; N.A.
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.

Disease Class: Lung adenocarcinoma [88]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: TAS6417
• Molecule Alteration: Duplication; p.S768_D770 (c.2302_2310)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: NCI-H1875 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: LXF 2378L cells; N.A.; .; N.A.
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.

Disease Class: Lung adenocarcinoma [88]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: TAS6417
• Molecule Alteration: Duplication; p.N771_H773 (c.2311_2319)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: NCI-H1875 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: LXF 2378L cells; N.A.; .; N.A.
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.

Trametinib/WZ4002

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [89]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Trametinib/WZ4002
• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: HCC4006 cells; Lung; Homo sapiens (Human); CVCL_1269
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: HCC2935 cells; Lung; Homo sapiens (Human); CVCL_1265
• In Vitro Model: DFCI81 cells; N.A.; .; N.A.
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vivo Model: Nu/Nu doxycycline-inducible transgenic mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay

Disease Class: Lung adenocarcinoma [89]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Trametinib/WZ4002
• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: HCC4006 cells; Lung; Homo sapiens (Human); CVCL_1269
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: HCC2935 cells; Lung; Homo sapiens (Human); CVCL_1265
• In Vitro Model: DFCI81 cells; N.A.; .; N.A.
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vivo Model: Nu/Nu doxycycline-inducible transgenic mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay

Investigative Drug(s) 11 drug(s) in total

Anti-EGFR treatment

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Non-small cell lung cancer [90]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Resistant Drug: Anti-EGFR treatment
• Molecule Alteration: Missense mutation; p.T790M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Longitudinal quantitative cfDNA analysis
• Experiment for Drug Resistance: Plasma-based tumor genotyping assay
• Mechanism Description: In patients with non-small cell lung cancer, the use of first-line anti-EGFR treatment in patients with activating EGFR mutations often leads to secondary resistance through an additional T790M mutation in EGFR in ~50% of initial responders.

Bevacizumab/Erlotinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [91]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Bevacizumab/Erlotinib
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Identified from the Human Clinical Data

Bevacizumab/Gefitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [92]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Bevacizumab/Gefitinib
• Molecule Alteration: Complex-indel; p.H773_V774delinsLM (c.2317_2322delinsCTTATG)
• Experimental Note: Identified from the Human Clinical Data

Cabozantinib/Erlotinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [93]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Cabozantinib/Erlotinib
• Molecule Alteration: Missense mutation; p.T790M (c.2369C>T)
• Experimental Note: Identified from the Human Clinical Data

EGFR TKIs

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Brain glioma [94]

• Resistant Disease: Brain glioma [ICD-11: 2A00.0]
• Resistant Drug: EGFR TKIs
• Molecule Alteration: IF-deletion; p.V30_V336 (c.88_1008)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; .
• Mechanism Description: The if-deletion p.V30_V336 (c.88_1008) in gene EGFR cause the resistance of EGFR TKIs by aberration of the drug's therapeutic target.

Disease Class: Brain glioma [95]

• Resistant Disease: Brain glioma [ICD-11: 2A00.0]
• Resistant Drug: EGFR TKIs
• Molecule Alteration: Copy number gain; .
• Experimental Note: Identified from the Human Clinical Data

Futuximab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [96]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Futuximab
• Molecule Alteration: Missense mutation; p.R451C (c.1351C>T)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Regulation; hsa01521
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EGFR cells; N.A.; .; N.A.
• In Vivo Model: Male BALB/c nude mouse; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay; FACS assay; Crystal violet staining assay
• Mechanism Description: Contrary to cetuximab and panitumumab, Sym004 effectively binds to and prevents activation of all the EGFR mutants. Sym004 effectively inhibits proliferation and EGFR downstream signaling in cetuximab-resistant derivatives harboring the S492R and G465R EGFR mutations. Sym004 causes profound and sustained regression in S492R-mutant EGFR and delays tumor growth in G465R-mutant EGFR in vivo.

Disease Class: Solid tumour/cancer [96]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Futuximab
• Molecule Alteration: Missense mutation; p.K467T (c.1400A>C)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Regulation; hsa01521
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EGFR cells; N.A.; .; N.A.
• In Vivo Model: Male BALB/c nude mouse; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay; FACS assay; Crystal violet staining assay
• Mechanism Description: Contrary to cetuximab and panitumumab, Sym004 effectively binds to and prevents activation of all the EGFR mutants. Sym004 effectively inhibits proliferation and EGFR downstream signaling in cetuximab-resistant derivatives harboring the S492R and G465R EGFR mutations. Sym004 causes profound and sustained regression in S492R-mutant EGFR and delays tumor growth in G465R-mutant EGFR in vivo.

Disease Class: Colorectal cancer [96]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Futuximab
• Molecule Alteration: Missense mutation; p.R451C (c.1351C>T)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Regulation; hsa01521
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EGFR cells; N.A.; .; N.A.
• In Vivo Model: Male BALB/c nude mouse; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay; FACS assay; Crystal violet staining assay
• Mechanism Description: Contrary to cetuximab and panitumumab, Sym004 effectively binds to and prevents activation of all the EGFR mutants. Sym004 effectively inhibits proliferation and EGFR downstream signaling in cetuximab-resistant derivatives harboring the S492R and G465R EGFR mutations. Sym004 causes profound and sustained regression in S492R-mutant EGFR and delays tumor growth in G465R-mutant EGFR in vivo.

Disease Class: Colorectal cancer [96]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Futuximab
• Molecule Alteration: Missense mutation; p.G465R (c.1393G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Regulation; hsa01521
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EGFR cells; N.A.; .; N.A.
• In Vivo Model: Male BALB/c nude mouse; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay; FACS assay; Crystal violet staining assay
• Mechanism Description: Contrary to cetuximab and panitumumab, Sym004 effectively binds to and prevents activation of all the EGFR mutants. Sym004 effectively inhibits proliferation and EGFR downstream signaling in cetuximab-resistant derivatives harboring the S492R and G465R EGFR mutations. Sym004 causes profound and sustained regression in S492R-mutant EGFR and delays tumor growth in G465R-mutant EGFR in vivo.

Disease Class: Colorectal cancer [96]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Futuximab
• Molecule Alteration: Missense mutation; p.K467T (c.1400A>C)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Regulation; hsa01521
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EGFR cells; N.A.; .; N.A.
• In Vivo Model: Male BALB/c nude mouse; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay; FACS assay; Crystal violet staining assay
• Mechanism Description: Contrary to cetuximab and panitumumab, Sym004 effectively binds to and prevents activation of all the EGFR mutants. Sym004 effectively inhibits proliferation and EGFR downstream signaling in cetuximab-resistant derivatives harboring the S492R and G465R EGFR mutations. Sym004 causes profound and sustained regression in S492R-mutant EGFR and delays tumor growth in G465R-mutant EGFR in vivo.

Disease Class: Colorectal cancer [96]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Futuximab
• Molecule Alteration: Missense mutation; p.S492R (c.1476C>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR signaling pathway; Regulation; hsa01521
• In Vitro Model: LIM1215 cells; Colon; Homo sapiens (Human); CVCL_2574
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EGFR cells; N.A.; .; N.A.
• In Vivo Model: Male BALB/c nude mouse; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay; FACS assay; Crystal violet staining assay
• Mechanism Description: Contrary to cetuximab and panitumumab, Sym004 effectively binds to and prevents activation of all the EGFR mutants. Sym004 effectively inhibits proliferation and EGFR downstream signaling in cetuximab-resistant derivatives harboring the S492R and G465R EGFR mutations. Sym004 causes profound and sustained regression in S492R-mutant EGFR and delays tumor growth in G465R-mutant EGFR in vivo.

Disease Class: Colorectal cancer [97]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Futuximab
• Molecule Alteration: Missense mutation; p.S492R (c.1476C>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: LS1034 cells; Colon; Homo sapiens (Human); CVCL_1382
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vitro Model: GEO cells; Colon; Homo sapiens (Human); CVCL_0271
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: SW948 cells; Colon; Homo sapiens (Human); CVCL_0632
• In Vitro Model: SW403 cells; Colon; Homo sapiens (Human); CVCL_0545
• In Vitro Model: SW837 cells; Colon; Homo sapiens (Human); CVCL_1729
• In Vitro Model: T84 cells; Colon; Homo sapiens (Human); CVCL_0555
• In Vitro Model: SW1463 cells; Rectum; Homo sapiens (Human); CVCL_1718
• In Vitro Model: H716 cells; Ascites; Homo sapiens (Human); CVCL_1581
• In Vitro Model: H508 cells; Abdominal wall; Homo sapiens (Human); CVCL_1564
• In Vitro Model: SNUC2A cells; Cecum; Homo sapiens (Human); CVCL_1709
• In Vitro Model: COLO678 cells; Colon; Homo sapiens (Human); CVCL_1129
• In Vitro Model: GP5D cells; Colon; Homo sapiens (Human); CVCL_1235
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 assay

PKI-587

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [98]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: PKI-587
• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Experimental Note: Identified from the Human Clinical Data

Staurosporine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [99]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Staurosporine
• Molecule Alteration: Missense mutation; p.T790M (c.2369C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Lung; .

TAS-121

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Colorectal cancer [100]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: TAS-121
• Molecule Alteration: Missense mutation; p.G719S (c.2155G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vivo Model: Male BALB/cA nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Disease Class: Lung adenocarcinoma [100]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: TAS-121
• Molecule Alteration: Missense mutation; p.G719S (c.2155G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vivo Model: Male BALB/cA nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Disease Class: Lung adenocarcinoma [100]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: TAS-121
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vivo Model: Male BALB/cA nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Unspecified CTLA4 antibody/Unspecified PD-1 antibody

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [101]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Unspecified CTLA4 antibody/Unspecified PD-1 antibody
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Identified from the Human Clinical Data

Unspecified PD-L1 antibody

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [101]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Unspecified PD-L1 antibody
• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Experimental Note: Identified from the Human Clinical Data

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Brain cancer [ICD-11: 2A00]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Nervous tissue
• The Specified Disease: Brain cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.30E-26; Fold-change: 6.21E-02; Z-score: 1.32E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.09E-05; Fold-change: 3.96E-01; Z-score: 1.90E+02
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.32E-04; Fold-change: 3.88E-01; Z-score: 1.69E+00
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Neuroectodermal tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.84E-08; Fold-change: -1.12E+00; Z-score: -4.45E+00

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.65E-01; Fold-change: -4.23E-02; Z-score: -8.52E-02
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.58E-03; Fold-change: -2.14E-01; Z-score: -3.48E-01

Melanoma [ICD-11: 2C30]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Skin
• The Specified Disease: Melanoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.60E-01; Fold-change: -3.39E-01; Z-score: -2.30E-01

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.04E-65; Fold-change: -8.87E-01; Z-score: -1.53E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.77E-16; Fold-change: -9.49E-01; Z-score: -1.79E+00

Prostate cancer [ICD-11: 2C82]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Prostate
• The Specified Disease: Prostate cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.43E-04; Fold-change: -5.92E-01; Z-score: -8.22E-01

References

• Ref 1: Phase I study of continuous afatinib (BIBW 2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitinib (LUX-Lung 4). Cancer Chemother Pharmacol. 2012 Apr;69(4):891-9. doi: 10.1007/s00280-011-1738-1. Epub 2011 Nov 10.
• Ref 2: The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor. Mol Cancer Ther. 2012 Mar;11(3):784-91. doi: 10.1158/1535-7163.MCT-11-0750. Epub 2012 Jan 6.
• Ref 3: Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1. Cell Rep. 2014 May 22;7(4):999-1008. doi: 10.1016/j.celrep.2014.04.014. Epub 2014 May 9.
• Ref 4: Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):E2127-33. doi: 10.1073/pnas.1203530109. Epub 2012 Jul 6.
• Ref 5: Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. Cancer Res. 2013 May 15;73(10):3051-61. doi: 10.1158/0008-5472.CAN-12-4136. Epub 2013 Mar 29.
• Ref 6: Clinical implications of T790M mutation in patients with acquired resistance to EGFR tyrosine kinase inhibitors. Lung Cancer. 2013 Nov;82(2):294-8. doi: 10.1016/j.lungcan.2013.08.023. Epub 2013 Sep 3.
• Ref 7: EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer .Cancer Discov. 2019 Feb;9(2):199-209. doi: 10.1158/2159-8290.CD-18-0598. Epub 2018 Nov 21. 10.1158/2159-8290.CD-18-0598
• Ref 8: The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical ModelsClin Cancer Res. 2016 Nov 15;22(22):5527-5538. doi: 10.1158/1078-0432.CCR-16-0569. Epub 2016 Oct 25.
• Ref 9: Heterogeneity of Acquired Resistance to Anti-EGFR Monoclonal Antibodies in Patients with Metastatic Colorectal Cancer. Clin Cancer Res. 2017 May 15;23(10):2414-2422. doi: 10.1158/1078-0432.CCR-16-1863. Epub 2016 Oct 25.
• Ref 10: Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment. Ann Oncol. 2015 Apr;26(4):731-736. doi: 10.1093/annonc/mdv005. Epub 2015 Jan 26.
• Ref 11: MicroRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation. Carcinogenesis. 2015 Mar;36(3):338-45. doi: 10.1093/carcin/bgu242. Epub 2014 Dec 10.
• Ref 12: [The effect and mechanism of microRNA-21 on cis-dichlorodiamineplatinum resistance in lung cancer cell strain]. Zhonghua Yi Xue Za Zhi. 2016 May 17;96(18):1454-8. doi: 10.3760/cma.j.issn.0376-2491.2016.18.014.
• Ref 13: Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 InhibitorsCancer Res. 2017 May 15;77(10):2712-2721. doi: 10.1158/0008-5472.CAN-16-3404. Epub 2017 Mar 31.
• Ref 14: Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutationsJ Clin Oncol. 2013 Sep 20;31(27):3327-34. doi: 10.1200/JCO.2012.44.2806. Epub 2013 Jul 1.
• Ref 15: EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIsClin Cancer Res. 2015 Dec 1;21(23):5305-13. doi: 10.1158/1078-0432.CCR-15-1046. Epub 2015 Jul 23.
• Ref 16: Management and future directions in non-small cell lung cancer with known activating mutationsAm Soc Clin Oncol Educ Book. 2014:e353-65. doi: 10.14694/EdBook_AM.2014.34.e353.
• Ref 17: Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trialsAnn Oncol. 2016 Mar;27(3):423-9. doi: 10.1093/annonc/mdv593. Epub 2016 Jan 13.
• Ref 18: Circulating-free DNA Mutation Associated with Response of Targeted Therapy in Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer. Chin Med J (Engl). 2017 Mar 5;130(5):522-529. doi: 10.4103/0366-6999.200542.
• Ref 19: MicroRNA-27b reverses docetaxel resistance of non-small cell lung carcinoma cells via targeting epithelial growth factor receptor. Mol Med Rep. 2016 Jul;14(1):949-54. doi: 10.3892/mmr.2016.5332. Epub 2016 May 24.
• Ref 20: LncRNA LOXL1-AS1/miR-let-7a-5p/EGFR-related pathway regulates the doxorubicin resistance of prostate cancer DU-145 cells. IUBMB Life. 2019 Oct;71(10):1537-1551. doi: 10.1002/iub.2075. Epub 2019 Jun 12.
• Ref 21: Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011 Mar 15;17(6):1616-22. doi: 10.1158/1078-0432.CCR-10-2692. Epub 2010 Dec 6.
• Ref 22: A noninvasive system for monitoring resistance to epidermal growth factor receptor tyrosine kinase inhibitors with plasma DNA. J Thorac Oncol. 2011 Oct;6(10):1639-48. doi: 10.1097/JTO.0b013e31822956e8.
• Ref 23: Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations. Cancer. 2013 Dec 15;119(24):4325-32. doi: 10.1002/cncr.28364. Epub 2013 Sep 16.
• Ref 24: Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011 Mar 23;3(75):75ra26. doi: 10.1126/scitranslmed.3002003.
• Ref 25: Erlotinib in African Americans with advanced non-small cell lung cancer: a prospective randomized study with genetic and pharmacokinetic analyses. Clin Pharmacol Ther. 2014 Aug;96(2):182-91. doi: 10.1038/clpt.2014.93. Epub 2014 Apr 29.
• Ref 26: Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open. 2016 May 11;1(3):e000060. doi: 10.1136/esmoopen-2016-000060. eCollection 2016.
• Ref 27: Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014 Aug;11(8):473-81. doi: 10.1038/nrclinonc.2014.104. Epub 2014 Jul 1.
• Ref 28: Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013 Aug;10(8):472-84. doi: 10.1038/nrclinonc.2013.110. Epub 2013 Jul 9.
• Ref 29: Mechanism of Resistance and Novel Targets Mediating Resistance to EGFR and c-Met Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. PLoS One. 2015 Aug 24;10(8):e0136155. doi: 10.1371/journal.pone.0136155. eCollection 2015.
• Ref 30: Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy. J Clin Oncol. 2008 Jun 1;26(16):2745-53. doi: 10.1200/JCO.2007.15.6695.
• Ref 31: Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial. J Thorac Oncol. 2010 Sep;5(9):1382-90. doi: 10.1097/JTO.0b013e3181eba657.
• Ref 32: Phase II trial of gefitinib and everolimus in advanced non-small cell lung cancer. J Thorac Oncol. 2010 Oct;5(10):1623-9. doi: 10.1097/JTO.0b013e3181ec1531.
• Ref 33: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005 Feb 24;352(8):786-92. doi: 10.1056/NEJMoa044238.
• Ref 34: EGFR mutation conferring primary resistance to gefitinib in non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):207-8. doi: 10.1056/NEJM200507143530217.
• Ref 35: Epidermal growth factor receptor mutations are associated with gefitinib sensitivity in non-small cell lung cancer in Japanese. Lung Cancer. 2006 Jan;51(1):71-7. doi: 10.1016/j.lungcan.2005.08.006. Epub 2005 Sep 29.
• Ref 36: Mechanisms of acquired resistance to EGFR-tyrosine kinase inhibitor in Korean patients with lung cancer. BMC Cancer. 2013 Dec 27;13:606. doi: 10.1186/1471-2407-13-606.
• Ref 37: EGFR-Driven Behavior and Intrapatient T790M Mutation Heterogeneity of Non-Small-Cell Carcinoma With Squamous Histology. J Clin Oncol. 2015 Nov 1;33(31):e115-8. doi: 10.1200/JCO.2013.49.5697. Epub 2014 Apr 21.
• Ref 38: Squamous Cell Carcinoma "Transformation" Concurrent with Secondary T790M Mutation in Resistant EGFR-Mutated Adenocarcinomas. J Thorac Oncol. 2016 Apr;11(4):e49-51. doi: 10.1016/j.jtho.2015.12.096. Epub 2015 Dec 30.
• Ref 39: Noninvasive monitoring of the genetic evolution of EGFR-mutant non-small-cell lung cancer by analyzing circulating tumor DNA during combination chemotherapy with gefitinib and pemetrexed or S-1. Onco Targets Ther. 2016 Aug 24;9:5287-95. doi: 10.2147/OTT.S105976. eCollection 2016.
• Ref 40: Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res. 2006 Nov 1;12(21):6494-501. doi: 10.1158/1078-0432.CCR-06-1570.
• Ref 41: Long Noncoding RNA LINC00460 Promotes the Gefitinib Resistance of Nonsmall Cell Lung Cancer Through Epidermal Growth Factor Receptor by Sponging miR-769-5p. DNA Cell Biol. 2019 Feb;38(2):176-183. doi: 10.1089/dna.2018.4462. Epub 2019 Jan 2.
• Ref 42: HOXA4-regulated miR-138 suppresses proliferation and gefitinib resistance in non-small cell lung cancer. Mol Genet Genomics. 2019 Feb;294(1):85-93. doi: 10.1007/s00438-018-1489-3. Epub 2018 Sep 8.
• Ref 43: Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013 May 2;497(7447):108-12. doi: 10.1038/nature12065. Epub 2013 Apr 7.
• Ref 44: MicroRNA-200a Targets EGFR and c-Met to Inhibit Migration, Invasion, and Gefitinib Resistance in Non-Small Cell Lung Cancer. Cytogenet Genome Res. 2015;146(1):1-8. doi: 10.1159/000434741. Epub 2015 Jul 11.
• Ref 45: The long non-coding RNA, GAS5, enhances gefitinib-induced cell death in innate EGFR tyrosine kinase inhibitor-resistant lung adenocarcinoma cells with wide-type EGFR via downregulation of the IGF-1R expression. J Hematol Oncol. 2015 Apr 29;8:43. doi: 10.1186/s13045-015-0140-6.
• Ref 46: MicroRNA expression profiles associated with acquired gefitinib-resistance in human lung adenocarcinoma cells. Mol Med Rep. 2015 Jan;11(1):333-40. doi: 10.3892/mmr.2014.2757. Epub 2014 Oct 23.
• Ref 47: MicroRNA-133b inhibits the growth of non-small-cell lung cancer by targeting the epidermal growth factor receptor. FEBS J. 2012 Oct;279(20):3800-12. doi: 10.1111/j.1742-4658.2012.08741.x. Epub 2012 Sep 11.
• Ref 48: Acquired C797S Mutation upon Treatment with a T790M-Specific Third-Generation EGFR Inhibitor (HM61713) in Non-Small Cell Lung Cancer. J Thorac Oncol. 2016 Apr;11(4):e45-7. doi: 10.1016/j.jtho.2015.12.093. Epub 2015 Dec 31.
• Ref 49: Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015 Jun;21(6):560-2. doi: 10.1038/nm.3854. Epub 2015 May 4.
• Ref 50: Mechanisms of Acquired Resistance to AZD9291: A Mutation-Selective, Irreversible EGFR Inhibitor. J Thorac Oncol. 2015 Dec;10(12):1736-44. doi: 10.1097/JTO.0000000000000688.
• Ref 51: MicroRNA-7 sensitizes non-small cell lung cancer cells to paclitaxel. Oncol Lett. 2014 Nov;8(5):2193-2200. doi: 10.3892/ol.2014.2500. Epub 2014 Sep 4.
• Ref 52: Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies .J Exp Clin Cancer Res. 2021 Oct 18;40(1):328. doi: 10.1186/s13046-021-02130-2. 10.1186/s13046-021-02130-2
• Ref 53: MiR-181b modulates chemosensitivity of glioblastoma multiforme cells to temozolomide by targeting the epidermal growth factor receptor. J Neurooncol. 2017 Jul;133(3):477-485. doi: 10.1007/s11060-017-2463-3. Epub 2017 May 13.
• Ref 54: MicroRNA-7 inhibits multiple oncogenic pathways to suppress HER2 Delta 16 mediated breast tumorigenesis and reverse trastuzumab resistance. PLoS One. 2014 Dec 22;9(12):e114419. doi: 10.1371/journal.pone.0114419. eCollection 2014.
• Ref 55: Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistanceClin Cancer Res. 2009 May 15;15(10):3484-94. doi: 10.1158/1078-0432.CCR-08-2904. Epub 2009 May 15.
• Ref 56: Small in-frame deletion in the epidermal growth factor receptor as a target for ZD6474Cancer Res. 2004 Dec 15;64(24):9101-4. doi: 10.1158/0008-5472.CAN-04-2360.
• Ref 57: miR-7 reverses the resistance to BRAFi in melanoma by targeting EGFR/IGF-1R/CRAF and inhibiting the MAPK and PI3K/AKT signaling pathways. Oncotarget. 2016 Aug 16;7(33):53558-53570. doi: 10.18632/oncotarget.10669.
• Ref 58: AC0010, an Irreversible EGFR Inhibitor Selectively Targeting Mutated EGFR and Overcoming T790M-Induced Resistance in Animal Models and Lung Cancer PatientsMol Cancer Ther. 2016 Nov;15(11):2586-2597. doi: 10.1158/1535-7163.MCT-16-0281. Epub 2016 Aug 29.
• Ref 59: EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF ReceptorCancer Res. 2016 Mar 15;76(6):1591-602. doi: 10.1158/0008-5472.CAN-15-2581. Epub 2016 Jan 29.
• Ref 60: Antitumor activity of selective MEK1/2 inhibitor AZD6244 in combination with PI3K/mTOR inhibitor BEZ235 in gefitinib-resistant NSCLC xenograft modelsJ Exp Clin Cancer Res. 2014 Jun 17;33(1):52. doi: 10.1186/1756-9966-33-52.
• Ref 61: EGFR Exon 20 Insertion Mutations Display Sensitivity to Hsp90 Inhibition in Preclinical Models and Lung AdenocarcinomasClin Cancer Res. 2018 Dec 15;24(24):6548-6555. doi: 10.1158/1078-0432.CCR-18-1541. Epub 2018 Aug 28.
• Ref 62: Activity of the Hsp90 inhibitor luminespib among non-small-cell lung cancers harboring EGFR exon 20 insertionsAnn Oncol. 2018 Oct 1;29(10):2092-2097. doi: 10.1093/annonc/mdy336.
• Ref 63: Pharmacological and Structural Characterizations of Naquotinib, a Novel Third-Generation EGFR Tyrosine Kinase Inhibitor, in EGFR-Mutated Non-Small Cell Lung CancerMol Cancer Ther. 2018 Apr;17(4):740-750. doi: 10.1158/1535-7163.MCT-17-1033. Epub 2018 Feb 21.
• Ref 64: Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancerNat Med. 2018 May;24(5):638-646. doi: 10.1038/s41591-018-0007-9. Epub 2018 Apr 23.
• Ref 65: Phase II study of the multitargeted tyrosine kinase inhibitor XL647 in patients with non-small-cell lung cancer. J Thorac Oncol. 2012 May;7(5):856-65. doi: 10.1097/JTO.0b013e31824c943f.
• Ref 66: Functional analysis of epidermal growth factor receptor (EGFR) mutations and potential implications for EGFR targeted therapyClin Cancer Res. 2009 Jan 15;15(2):460-7. doi: 10.1158/1078-0432.CCR-08-1757.
• Ref 67: The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATPProc Natl Acad Sci U S A. 2008 Feb 12;105(6):2070-5. doi: 10.1073/pnas.0709662105. Epub 2008 Jan 28.
• Ref 68: BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal CancersMol Cancer Ther. 2015 Oct;14(10):2187-97. doi: 10.1158/1535-7163.MCT-15-0262. Epub 2015 Jul 24.
• Ref 69: CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activityCancer Res. 2010 May 1;70(9):3647-56. doi: 10.1158/0008-5472.CAN-09-3360. Epub 2010 Apr 13.
• Ref 70: YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non-Small Cell Lung CancerClin Cancer Res. 2019 Apr 15;25(8):2575-2587. doi: 10.1158/1078-0432.CCR-18-2906. Epub 2019 Jan 22.
• Ref 71: Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun. 2016 Jun 10;7:11815. doi: 10.1038/ncomms11815.
• Ref 72: Tumor Evolution as a Therapeutic Target. Cancer Discov. 2017 Jul 20. doi: 10.1158/2159-8290.CD-17-0343. Online ahead of print.
• Ref 73: Pharmacological characterization of MP-412 (AV-412), a dual epidermal growth factor receptor and ErbB2 tyrosine kinase inhibitorCancer Sci. 2007 Dec;98(12):1977-84. doi: 10.1111/j.1349-7006.2007.00613.x. Epub 2007 Sep 18.
• Ref 74: AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastasesSci Transl Med. 2016 Dec 7;8(368):368ra172. doi: 10.1126/scitranslmed.aag0976.
• Ref 75: SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung CancerCancer Res. 2017 Jun 1;77(11):2990-3000. doi: 10.1158/0008-5472.CAN-16-2300. Epub 2017 Apr 17.
• Ref 76: Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitorsNature. 2016 Jun 2;534(7605):129-32. doi: 10.1038/nature17960. Epub 2016 May 25.
• Ref 77: Resistance to an irreversible epidermal growth factor receptor (EGFR) inhibitor in EGFR-mutant lung cancer reveals novel treatment strategiesCancer Res. 2007 Nov 1;67(21):10417-27. doi: 10.1158/0008-5472.CAN-07-1248.
• Ref 78: EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR InhibitorsClin Cancer Res. 2015 Sep 1;21(17):3913-23. doi: 10.1158/1078-0432.CCR-14-2789. Epub 2015 May 6.
• Ref 79: ER2, a novel human anti-EGFR monoclonal antibody inhibit tumor activity in non-small cell lung cancer modelsLung Cancer. 2016 May;95:57-64. doi: 10.1016/j.lungcan.2016.02.013. Epub 2016 Feb 27.
• Ref 80: The HSP90 inhibitor ganetespib potentiates the antitumor activity of EGFR tyrosine kinase inhibition in mutant and wild-type non-small cell lung cancerTarget Oncol. 2015 Jun;10(2):235-45. doi: 10.1007/s11523-014-0329-6. Epub 2014 Aug 1.
• Ref 81: A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant GliomaClin Cancer Res. 2018 Aug 1;24(15):3611-3631. doi: 10.1158/1078-0432.CCR-17-0126. Epub 2018 Apr 27.
• Ref 82: Single and Dual Targeting of Mutant EGFR with an Allosteric InhibitorCancer Discov. 2019 Jul;9(7):926-943. doi: 10.1158/2159-8290.CD-18-0903. Epub 2019 May 15.
• Ref 83: MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutationsSci Transl Med. 2016 Feb 3;8(324):324ra14. doi: 10.1126/scitranslmed.aad5640.
• Ref 84: Molecular Basis for Necitumumab Inhibition of EGFR Variants Associated with Acquired Cetuximab ResistanceMol Cancer Ther. 2018 Feb;17(2):521-531. doi: 10.1158/1535-7163.MCT-17-0575. Epub 2017 Nov 20.
• Ref 85: Discovery of a Potent and Mutant-Selective EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Lung CancerTarget Oncol. 2018 Jun;13(3):389-398. doi: 10.1007/s11523-018-0568-z.
• Ref 86: Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical ModelsCancer Res. 2015 Jun 15;75(12):2489-500. doi: 10.1158/0008-5472.CAN-14-3167. Epub 2015 Apr 13.
• Ref 87: TAE226, a Bis-Anilino Pyrimidine Compound, Inhibits the EGFR-Mutant Kinase Including T790M Mutant to Show Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer CellsPLoS One. 2015 Jun 19;10(6):e0129838. doi: 10.1371/journal.pone.0129838. eCollection 2015.
• Ref 88: TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion MutationsMol Cancer Ther. 2018 Aug;17(8):1648-1658. doi: 10.1158/1535-7163.MCT-17-1206. Epub 2018 May 10.
• Ref 89: Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung CancerCancer Discov. 2015 Sep;5(9):960-971. doi: 10.1158/2159-8290.CD-15-0063. Epub 2015 Jun 2.
• Ref 90: Capturing tumor heterogeneity and clonal evolution in solid cancers using circulating tumor DNA analysis. Pharmacol Ther. 2017 Jun;174:22-26. doi: 10.1016/j.pharmthera.2017.02.003. Epub 2017 Feb 3.
• Ref 91: Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trialLancet Respir Med. 2017 May;5(5):435-444. doi: 10.1016/S2213-2600(17)30129-7. Epub 2017 Apr 10.
• Ref 92: Case Report: Osimertinib achieved remarkable and sustained disease control in an advanced non-small-cell lung cancer harboring EGFR H773L/V774M mutation complexLung Cancer. 2018 Jul;121:1-4. doi: 10.1016/j.lungcan.2018.04.006. Epub 2018 Apr 5.
• Ref 93: Phase II Trial of Cabozantinib Plus Erlotinib in Patients With Advanced Epidermal Growth Factor Receptor (EGFR)-Mutant Non-small Cell Lung Cancer With Progressive Disease on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy: A California Cancer Consortium Phase II Trial (NCI 9303)Front Oncol. 2019 Mar 11;9:132. doi: 10.3389/fonc.2019.00132. eCollection 2019.
• Ref 94: Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034J Clin Oncol. 2009 Mar 10;27(8):1268-74. doi: 10.1200/JCO.2008.17.5984. Epub 2009 Feb 9.
• Ref 95: Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01Clin Cancer Res. 2005 Nov 1;11(21):7841-50. doi: 10.1158/1078-0432.CCR-05-0421.
• Ref 96: The First-in-class Anti-EGFR Antibody Mixture Sym004 Overcomes Cetuximab Resistance Mediated by EGFR Extracellular Domain Mutations in Colorectal CancerClin Cancer Res. 2016 Jul 1;22(13):3260-7. doi: 10.1158/1078-0432.CCR-15-2400. Epub 2016 Feb 17.
• Ref 97: Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal CancerCancer Discov. 2015 Jun;5(6):598-609. doi: 10.1158/2159-8290.CD-14-1432. Epub 2015 May 11.
• Ref 98: Chemotherapy-induced epidermal growth factor receptor activation determines response to combined gefitinib/chemotherapy treatment in non-small cell lung cancer cellsMol Cancer Ther. 2006 May;5(5):1154-65. doi: 10.1158/1535-7163.MCT-05-0446.
• Ref 99: A systematic profile of clinical inhibitors responsive to EGFR somatic amino acid mutations in lung cancer: implication for the molecular mechanism of drug resistance and sensitivityAmino Acids. 2014 Jul;46(7):1635-48. doi: 10.1007/s00726-014-1716-0.
• Ref 100: TAS-121, A Selective Mutant EGFR Inhibitor, Shows Activity Against Tumors Expressing Various EGFR Mutations Including T790M and Uncommon Mutations G719XMol Cancer Ther. 2019 May;18(5):920-928. doi: 10.1158/1535-7163.MCT-18-0645. Epub 2019 Mar 14.
• Ref 101: EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancerAnn Oncol. 2019 Aug 1;30(8):1311-1320. doi: 10.1093/annonc/mdz141.