Molecule Information

General Information of the Molecule (ID: Mol04140)

• Name: Oncogenic epidermal growth factor receptor (EGFR) ,Homo sapiens
• Synonyms: Proto-oncogene c-ErbB-1; Receptor tyrosine-protein kinase erbB-1
• 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 (PubMed:10805725, PubMed:27153536, PubMed:2790960, PubMed:35538033). Known ligands include EGF, TGFA/TGF- alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF (PubMed:12297049, PubMed:15611079, PubMed:17909029, PubMed:20837704, PubMed:27153536, PubMed:2790960, PubMed:7679104, PubMed:8144591, PubMed:9419975). 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 (PubMed:27153536). May also activate the NF-kappa-B signaling cascade (PubMed:11116146). 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 (PubMed:11602604). Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin (PubMed:11483589). 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 (PubMed:20462955). Plays a role in enhancing learning and memory performance (By similarity). Plays a role in mammalian pain signaling (long-lasting hypersensitivity) (By similarity). .; Isoform 2 may act as an antagonist of EGF action.; (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins. .
• 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

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 12 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 [ICD-11: 2C25.0] [5]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Afatinib
• Molecule Alteration: Missense mutation; Exon 20 insertion mutations
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-Akt signaling pathway; Inhibition; hsa04151
• In Vitro Model: Ba/F3 murine cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: Bosc23 cells; Fetal kidney; Homo sapiens (Human); CVCL_4401
• Experiment for Molecule Alteration: GeneSeq assay
• Experiment for Drug Resistance: Cell proliferation assay; Immunoblotting assay
• Mechanism Description: Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [5]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Afatinib
• Molecule Alteration: Missense mutation; Exon 20 insertion mutations
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-Akt signaling pathway; Inhibition; hsa04151
• In Vitro Model: Ba/F3 murine cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: Bosc23 cells; Fetal kidney; Homo sapiens (Human); CVCL_4401
• Experiment for Molecule Alteration: GeneSeq assay
• Experiment for Drug Resistance: Cell proliferation assay; Immunoblotting assay
• Mechanism Description: Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.

Cetuximab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.0] [6]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Sensitive Drug: Cetuximab
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: EGF-EGFR signaling pathway; Regulation; N.A.
• In Vivo Model: Mouse model; Mus musculus
• Experiment for Molecule Alteration: Immunoprecipitation assay; LC-MS/MS analysis
• Experiment for Drug Resistance: Cellular ROS and lipid peroxidation level assay; LOXL3 enzymatic assay; In vitro kinase assay
• Mechanism Description: To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.00] [7]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Resistant Drug: Cisplatin
• Molecule Alteration: phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCA-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213A-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213B-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell cycle distribution assay; Colony formation assay
• Mechanism Description: The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.

Erlotinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [5]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Erlotinib
• Molecule Alteration: Missense mutation; EGFR-K745_E746insIPVAIK; Exon 19 deletion, L858R, L861Q, G719S, A763_Y764insFQEA
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-Akt signaling pathway; Inhibition; hsa04151
• In Vitro Model: Ba/F3 murine cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: Bosc23 cells; Fetal kidney; Homo sapiens (Human); CVCL_4401
• Experiment for Molecule Alteration: GeneSeq assay
• Experiment for Drug Resistance: Cell proliferation assay; Immunoblotting assay
• Mechanism Description: Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [5]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Erlotinib
• Molecule Alteration: Missense mutation; EGFR-K745_E746insIPVAIK; Exon 19 deletion, L858R, L861Q, G719S, A763_Y764insFQEA
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-Akt signaling pathway; Inhibition; hsa04151
• In Vitro Model: Ba/F3 murine cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: Bosc23 cells; Fetal kidney; Homo sapiens (Human); CVCL_4401
• Experiment for Molecule Alteration: GeneSeq assay
• Experiment for Drug Resistance: Cell proliferation assay; Immunoblotting assay
• Mechanism Description: Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.00] [7]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Sensitive Drug: Erlotinib
• Molecule Alteration: phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCA-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213A-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213B-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell cycle distribution assay; Colony formation assay
• Mechanism Description: The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.00] [7]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Resistant Drug: Fluorouracil
• Molecule Alteration: phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCA-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213A-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213B-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell cycle distribution assay; Colony formation assay
• Mechanism Description: The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.

Fulvestrant

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Triple-negative breast cancer [ICD-11: 2C60.9] [8]

• Resistant Disease: Triple-negative breast cancer [ICD-11: 2C60.9]
• Resistant Drug: Fulvestrant
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR/HER2 signaling pathway; Regulation; N.A.
• In Vitro Model: MCF7 (Ful-R) cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Mechanism Description: In this study, we investigated the molecular mechanism underlying the loss of ER, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ER proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R.

Disease Class: Triple-negative breast cancer [ICD-11: 2C60.9] [8]

• Resistant Disease: Triple-negative breast cancer [ICD-11: 2C60.9]
• Resistant Drug: Fulvestrant
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR/HER2 signaling pathway; Regulation; N.A.
• In Vitro Model: MCF7 (Ful-R) cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Mechanism Description: In this study, we investigated the molecular mechanism underlying the loss of ER, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ER proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R.

Gefitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [9]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT1 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [9]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC-9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT2 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [9]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H3255 cells; Lung; Homo sapiens (Human); CVCL_6831
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT3 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [9]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_B0JT
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT4 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [9]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Male nude mice; Mice
• Experiment for Molecule Alteration: CE-TOF/MS
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT5 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.00] [7]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Resistant Drug: Gemcitabine
• Molecule Alteration: phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KKU-213A-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell cycle distribution assay; Colony formation assay
• Mechanism Description: The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.00] [7]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Resistant Drug: Gemcitabine
• Molecule Alteration: phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCA-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213B-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell cycle distribution assay; Colony formation assay
• Mechanism Description: The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.0] [7]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: CCA-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Protein component assay; Western blot assay
• Mechanism Description: The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem. EGFR is a potential target molecule for reducing Gem resistance and enhancing its anti-tumor effects in patients with CCA.

Ivermectin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [ICD-11: 2A20.0] [10]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Sensitive Drug: Ivermectin
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR/STAT3/ERK signalling pathway; Regulation; N.A.
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: It was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML.

Lenvatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.0] [6]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Sensitive Drug: Lenvatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: EGF-EGFR signaling pathway; Regulation; N.A.
• In Vivo Model: Mouse model; Mus musculus
• Experiment for Molecule Alteration: Immunoprecipitation assay; LC-MS/MS analysis
• Experiment for Drug Resistance: Cellular ROS and lipid peroxidation level assay; LOXL3 enzymatic assay; In vitro kinase assay
• Mechanism Description: To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity.

Osimertinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [5]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Osimertinib
• Molecule Alteration: Missense mutation; Exon 20 insertion mutations
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-Akt signaling pathway; Inhibition; hsa04151
• In Vitro Model: Ba/F3 murine cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: Bosc23 cells; Fetal kidney; Homo sapiens (Human); CVCL_4401
• Experiment for Molecule Alteration: GeneSeq assay
• Experiment for Drug Resistance: Cell proliferation assay; Immunoblotting assay
• Mechanism Description: Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [5]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Osimertinib
• Molecule Alteration: Missense mutation; Exon 20 insertion mutations
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-Akt signaling pathway; Inhibition; hsa04151
• In Vitro Model: Ba/F3 murine cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: Bosc23 cells; Fetal kidney; Homo sapiens (Human); CVCL_4401
• Experiment for Molecule Alteration: GeneSeq assay
• Experiment for Drug Resistance: Cell proliferation assay; Immunoblotting assay
• Mechanism Description: Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.

Regorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.0] [2]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Resistant Drug: Regorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: RAS/RAF/ERK signaling pathway; Activation; hsa04010
• In Vitro Model: 7721-R cells; Liver; Homo sapiens (Human); N.A.
• In Vitro Model: 97H-R cells; Liver; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Annexin V-FITC/PI double-staining assay; Flow cytometry assay; Colony formation assay; CCK8 assay
• Mechanism Description: The expression of EGFR, a member of the receptor tyrosine kinase (RTK) family, was significantly increased in acquired regorafenib-resistant HCC cells compared with parental cells. Pharmacological inhibition of EGFR with gefitinib restored the sensitivity of regorafenib-resistant HCC cells to regorafenib. In a xenograft mouse model, gefitinib sensitized resistant tumors to regorafenib. Additionally, levels of RAS, RAF, and P-ERK1/2, components of the downstream EGFR signaling pathway, were positively associated with EGFR expression. EGFR overexpression promotes acquired resistance to regorafenib through RAS/RAF/ERK bypass activation in HCC.

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.0] [2]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Resistant Drug: Regorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: RAS/RAF/ERK signaling pathway; Activation; hsa04010
• In Vitro Model: SMMC-7721 cells; Liver; Homo sapiens (Human); CVCL_0534
• In Vitro Model: MHCC97H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vivo Model: BALB/c nude xenograft model; Mus musculus
• Experiment for Molecule Alteration: High-throughput proteomics assay
• Experiment for Drug Resistance: Direct microscopic assay; CCK8 assay; Colony formation assay; Annexin V-FITC/propidium iodide double staining assay; Cell cycle assay; Western blot assay; A xenograft model assay
• Mechanism Description: The expression of EGFR, a member of the receptor tyrosine kinase (RTK) family, was significantly increased in acquired regorafenib-resistant HCC cells compared with parental cells. Pharmacological inhibition of EGFR with gefitinib restored the sensitivity of regorafenib-resistant HCC cells to regorafenib. In a xenograft mouse model, gefitinib sensitized resistant tumors to regorafenib. Additionally, levels of RAS, RAF, and P-ERK1/2, components of the downstream EGFR signaling pathway, were positively associated with EGFR expression.

Clinical Trial Drug(s) 1 drug(s) in total

Flumatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [ICD-11: 2A20.0] [10]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Flumatinib
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR/STAT3/ERK signalling pathway; Regulation; N.A.
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins.

Investigative Drug(s) 1 drug(s) in total

Erlotinib/Gemcitabine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.00] [7]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.00]
• Sensitive Drug: Erlotinib/Gemcitabine
• Molecule Alteration: phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCA-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213A-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• In Vitro Model: KKU-213B-GemR cells; Bile duct; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell cycle distribution assay; Colony formation assay
• Mechanism Description: The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.

References

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