Molecule Information

General Information of the Molecule (ID: Mol00034)

• Name: Serine/threonine-protein kinase B-raf (BRAF) ,Homo sapiens
• Synonyms: Proto-oncogene B-Raf; p94; v-Raf murine sarcoma viral oncogene homolog B1; BRAF1; RAFB1
• Molecule Type: Protein
• Gene Name: BRAF
• Gene ID: 673
• Location: chr7:140719327-140924929[-]
• Sequence:
  MAALSGGGGGGAEPGQALFNGDMEPEAGAGAGAAASSAADPAIPEEVWNIKQMIKLTQEH
  IEALLDKFGGEHNPPSIYLEAYEEYTSKLDALQQREQQLLESLGNGTDFSVSSSASMDTV
  TSSSSSSLSVLPSSLSVFQNPTDVARSNPKSPQKPIVRVFLPNKQRTVVPARCGVTVRDS
  LKKALMMRGLIPECCAVYRIQDGEKKPIGWDTDISWLTGEELHVEVLENVPLTTHNFVRK
  TFFTLAFCDFCRKLLFQGFRCQTCGYKFHQRCSTEVPLMCVNYDQLDLLFVSKFFEHHPI
  PQEEASLAETALTSGSSPSAPASDSIGPQILTSPSPSKSIPIPQPFRPADEDHRNQFGQR
  DRSSSAPNVHINTIEPVNIDDLIRDQGFRGDGGSTTGLSATPPASLPGSLTNVKALQKSP
  GPQRERKSSSSSEDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFGTVYKGKWHGDV
  AVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGYSTKPQLAIVTQWCEGSSLYHH
  LHIIETKFEMIKLIDIARQTAQGMDYLHAKSIIHRDLKSNNIFLHEDLTVKIGDFGLATV
  KSRWSGSHQFEQLSGSILWMAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNIN
  NRDQIIFMVGRGYLSPDLSKVRSNCPKAMKRLMAECLKKKRDERPLFPQILASIELLARS
  LPKIHRSASEPSLNRAGFQTEDFSLYACASPKTPIQAGGYGAFPVH
• 3D-structure: PDB ID: 6Q0K; Classification: Signaling protein/transferase; Method: electron microscopy; Resolution: 6.80 Å
• Function: Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus (Probable). Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway. May play a role in the postsynaptic responses of hippocampal neurons.
• Uniprot ID: BRAF_HUMAN
• Ensembl ID: ENSG00000157764
• HGNC ID: HGNC:1097

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

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 13 drug(s) in total

Binimetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Binimetinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cutaneous melanoma tissue; N.A.
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway

Disease Class: Melanoma [ICD-11: 2C30.0] [3]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Binimetinib
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Skin sample; N.A.
• In Vivo Model: Mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Crystal violet staining assay

Disease Class: Melanoma [ICD-11: 2C30.0] [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Binimetinib
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cutaneous melanoma tissue; N.A.
• Mechanism Description: The missense mutation p.V600X (c.1798_1800) in gene BRAF cause the sensitivity of Binimetinib by unusual activation of pro-survival pathway

Cetuximab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [4]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Cetuximab
• Molecule Alteration: Missense mutation; p.V600E
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• 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.

Dabrafenib/Trametinib

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: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Disease Class: Melanoma [ICD-11: 2C30.0] [6]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Disease Class: Thyroid gland cancer [ICD-11: 2D10.0] [7]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Disease Class: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01] [8]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Disease Class: Salivary gland adenoid cystic carcinoma [ICD-11: 2E60.0] [9]

• Sensitive Disease: Salivary gland adenoid cystic carcinoma [ICD-11: 2E60.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Human laryngeal cells isolates; N.A.
• Experiment for Molecule Alteration: ctDNA sequencing assay

Disease Class: Melanoma [ICD-11: 2C30.0] [10]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [11]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.0] [12]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [13]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [14]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Colorectum; N.A.
• In Vivo Model: Patient-Derived xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Reverse-phase protein array (RPPA) analysis; Targeted next-generation sequencing (NGS) assay
• Experiment for Drug Resistance: Immunohistochemistry assay

Disease Class: Melanoma [ICD-11: 2C30.0] [10]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [13]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [14]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Colorectum; N.A.
• In Vivo Model: Patient-Derived xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Reverse-phase protein array (RPPA) analysis; Targeted next-generation sequencing (NGS) assay
• Experiment for Drug Resistance: Immunohistochemistry assay

Disease Class: Melanoma [ICD-11: 2C30.0] [15]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [16]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

Disease Class: Metastatic neuroendocrine carcinoma [ICD-11: 2D4Y.0] [17]

• Sensitive Disease: Metastatic neuroendocrine carcinoma [ICD-11: 2D4Y.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1406G>C)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Disease Class: Pleomorphic xanthoastrocytoma [ICD-11: 2A00.0Y] [8]

• Sensitive Disease: Pleomorphic xanthoastrocytoma [ICD-11: 2A00.0Y]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Inhibition; hsa04210
• In Vitro Model: Brain; N.A.

Disease Class: Metastatic neuroendocrine carcinoma [ICD-11: 2D4Y.0] [17]

• Sensitive Disease: Metastatic neuroendocrine carcinoma [ICD-11: 2D4Y.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Disease Class: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01] [18]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600D (c.1799_1800delTGinsAC)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BRAF/MEK/MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Brain; N.A.

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [19]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.G469A (c.1406G>C)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Inhibition; hsa04210
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The ERK pathway is the major deregulated pathway associated with BRAF-mutated cancers. ERK pathway inhibition has been shown to have anti-proliferative effects in cells harboring both kinase-activating and impairing BRAF mutations. The combination of Trametinib and Dabrafenib leads to more prolonged ERK inhibition and has anti-proliferative and pro-apoptotic effects in cells harboring both types of non-V600 BRAF mutations.

Disease Class: Melanoma [ICD-11: 2C30.0] [20]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Dabrafenib/Trametinib
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

Erlotinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7] [21]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: Erlotinib
• Molecule Alteration: Mutation; .
• 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.

Fluorouracil

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [22]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT asssay; Innocyte invasion assay
• Mechanism Description: microRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic kRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 kRAS WT cells phenocopied kRAS mutation, increased kRAS activity and ERk and AkT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing kRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial-mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells.

Gefitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7] [21]

• Resistant Disease: EGFR-mutant non-small cell lung cancer [ICD-11: 2C25.7]
• Resistant Drug: Gefitinib
• Molecule Alteration: Mutation; .
• 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.

Imatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastrointestinal stromal cancer [ICD-11: 2B5B.1] [23]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.V600E
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: RAS/RAF/Mek/ERK signaling pathway; Activation; hsa04010
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: High-performance liquid chromatography screening assay
• Mechanism Description: This finding, in combination with the loss of kIT expression, suggests the possibility of activation of RAS-RAF-MEk-ERk pathways driven by a kIT-independent oncogenic mechanism. Most mutations lie within the kinase domain with a single nucleotide substitution at position 1799 in exon 15, leading to the V600E amino-acid substitution (98 %).

Nivolumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Melanoma [ICD-11: 2C30.0] [24]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Nivolumab
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• 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: Melanoma [ICD-11: 2C30.0] [24]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Nivolumab
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Experimental Note: Identified from the Human Clinical Data

Panitumumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [4]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Panitumumab
• Molecule Alteration: Missense mutation; p.V600E
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• 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 [ICD-11: 2D85.0] [25]

• Resistant Disease: Metastatic colorectal cancer [ICD-11: 2D85.0]
• Resistant Drug: Panitumumab
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: RAS/MEk/ERK signaling pathway; Inhibition; hsa04010
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Mechanism Description: Mutations in kRAS, NRAS, and BRAF and amplification of ERBB2 and MET drive primary (de novo) resistance to anti-EGFR treatment.

Regorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastrointestinal stromal tumor [ICD-11: 2B5B.0] [26]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Resistant Drug: Regorafenib
• Molecule Alteration: Other; .
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Metastatic GI stromal tumor tissue; N.A.
• Mechanism Description: The mutation in gene BRAF cause the resistance of Regorafenib by unusual activation of pro-survival pathway.

Trametinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0] [27]

• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Resistant Drug: Trametinib
• Molecule Alteration: Missense mutation; p.K601E (c.1801A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vitro Model: NT-3 cells; Lymph node; Homo sapiens (Human); CVCL_VG81
• Experiment for Drug Resistance: BioRad TC20 automated cell counter assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [28]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.L597Q (c.1790T>A)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Melanoma [ICD-11: 2C30.0] [29]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.K601E (c.1801A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Melanoma thyroid metastasis; N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: The missense mutation p.K601E (c.1801A>G) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Melanoma [ICD-11: 2C30.0] [30]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.K601E (c.1801A>G)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Melanoma [ICD-11: 2C30.0] [30]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.L597R (c.1790T>G)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole-gene resequencing assay

Disease Class: Melanoma [ICD-11: 2C30.0] [30]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.V600R (c.1798_1799delGTinsAG)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [31]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.G466V (c.1397G>T)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Activation; hsa04210
• 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: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: HTB-56 cells; Pleural effusion; Homo sapiens (Human); CVCL_0236
• In Vitro Model: HTB-38 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HTB-183 cells; Lymph node; Homo sapiens (Human); CVCL_1577
• In Vitro Model: H661 cells; Lymph node; Homo sapiens (Human); CVCL_1577
• In Vitro Model: H508 cells; Abdominal wall; Homo sapiens (Human); CVCL_1564
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vitro Model: H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CRL-5944 cells; Ascites; Homo sapiens (Human); CVCL_1551
• In Vitro Model: CRL-5885 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: CRL-5883 cells; Pleural effusion; Homo sapiens (Human); CVCL_1483
• In Vitro Model: CRL-5868 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CRL-5803 cells; Lymph node; Homo sapiens (Human); CVCL_0060
• In Vitro Model: CCL-253 cells; Abdominal wall; Homo sapiens (Human); CVCL_1564
• In Vitro Model: CCL-185 cells; Bowel; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Calu-6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Researchers defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [31]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.G596R (c.1786G>C)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Activation; hsa04210
• 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: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: HTB-56 cells; Pleural effusion; Homo sapiens (Human); CVCL_0236
• In Vitro Model: HTB-38 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HTB-183 cells; Lymph node; Homo sapiens (Human); CVCL_1577
• In Vitro Model: H661 cells; Lymph node; Homo sapiens (Human); CVCL_1577
• In Vitro Model: H508 cells; Abdominal wall; Homo sapiens (Human); CVCL_1564
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vitro Model: H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CRL-5944 cells; Ascites; Homo sapiens (Human); CVCL_1551
• In Vitro Model: CRL-5885 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: CRL-5883 cells; Pleural effusion; Homo sapiens (Human); CVCL_1483
• In Vitro Model: CRL-5868 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CRL-5803 cells; Lymph node; Homo sapiens (Human); CVCL_0060
• In Vitro Model: CCL-253 cells; Abdominal wall; Homo sapiens (Human); CVCL_1564
• In Vitro Model: CCL-185 cells; Bowel; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Calu-6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Researchers defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [31]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.G466V (c.1397G>T)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Activation; hsa04210
• 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: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: HTB-56 cells; Pleural effusion; Homo sapiens (Human); CVCL_0236
• In Vitro Model: HTB-38 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HTB-183 cells; Lymph node; Homo sapiens (Human); CVCL_1577
• In Vitro Model: H661 cells; Lymph node; Homo sapiens (Human); CVCL_1577
• In Vitro Model: H508 cells; Abdominal wall; Homo sapiens (Human); CVCL_1564
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vitro Model: H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CRL-5944 cells; Ascites; Homo sapiens (Human); CVCL_1551
• In Vitro Model: CRL-5885 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: CRL-5883 cells; Pleural effusion; Homo sapiens (Human); CVCL_1483
• In Vitro Model: CRL-5868 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CRL-5803 cells; Lymph node; Homo sapiens (Human); CVCL_0060
• In Vitro Model: CCL-253 cells; Abdominal wall; Homo sapiens (Human); CVCL_1564
• In Vitro Model: CCL-185 cells; Bowel; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Calu-6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Researchers defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [32]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Complex-indel; p.L485_P490delinsY (c.1453_1470delinsTAT)
• Experimental Note: Revealed Based on the Cell Line Data
• 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: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: OV-90 cells; Ascites; Homo sapiens (Human); CVCL_3768
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vivo Model: NIH nude rat xenograft model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay

Disease Class: Ovarian cancer [ICD-11: 2C73.0] [32]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: IF-deletion; p.N486_P490delNVTAP (c.1457_1471del15)
• Experimental Note: Revealed Based on the Cell Line Data
• 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: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: OV-90 cells; Ascites; Homo sapiens (Human); CVCL_3768
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vivo Model: NIH nude rat xenograft model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay

Disease Class: Melanoma [ICD-11: 2C30.0] [33]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.L597V (c.1789C>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; N.A.
• Experiment for Molecule Alteration: Tumour genotyping assay
• Mechanism Description: The missense mutation p.L597V (c.1789C>G) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [29]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Melanoma thyroid metastasis; N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: The missense mutation p.L597S (c.1789_1790delCTinsTC) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [29]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.L597R (c.1790T>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Melanoma thyroid metastasis; N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: The missense mutation p.L597R (c.1790T>G) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [29]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.K601E (c.1801A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Melanoma thyroid metastasis; N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: The missense mutation p.K601E (c.1801A>G) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Melanoma [ICD-11: 2C30.0] [29]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Melanoma thyroid metastasis; N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: The missense mutation p.L597S (c.1789_1790delCTinsTC) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Melanoma [ICD-11: 2C30.0] [31]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.D594G (c.1781A>G)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Activation; hsa04210
• 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: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: HTB-56 cells; Pleural effusion; Homo sapiens (Human); CVCL_0236
• In Vitro Model: HTB-38 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HTB-183 cells; Lymph node; Homo sapiens (Human); CVCL_1577
• In Vitro Model: H661 cells; Lymph node; Homo sapiens (Human); CVCL_1577
• In Vitro Model: H508 cells; Abdominal wall; Homo sapiens (Human); CVCL_1564
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vitro Model: H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CRL-5944 cells; Ascites; Homo sapiens (Human); CVCL_1551
• In Vitro Model: CRL-5885 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: CRL-5883 cells; Pleural effusion; Homo sapiens (Human); CVCL_1483
• In Vitro Model: CRL-5868 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CRL-5803 cells; Lymph node; Homo sapiens (Human); CVCL_0060
• In Vitro Model: CCL-253 cells; Abdominal wall; Homo sapiens (Human); CVCL_1564
• In Vitro Model: CCL-185 cells; Bowel; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Calu-6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Researchers defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

Disease Class: Bladder cancer [ICD-11: 2C94.0] [34]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Other; .
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Melanoma [ICD-11: 2C30.0] [3]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Skin sample; N.A.
• In Vivo Model: Mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Crystal violet staining assay

Disease Class: Melanoma [ICD-11: 2C30.0] [35]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.D594V (c.1781A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The missense mutation p.D594V (c.1781A>T) in gene BRAF cause the sensitivity of Trametinib by unusual activation of pro-survival pathway

Disease Class: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0] [32]

• Sensitive Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Complex-indel; p.V487_P492delinsA (c.1460_1474del15)
• Experimental Note: Revealed Based on the Cell Line Data
• 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: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: OV-90 cells; Ascites; Homo sapiens (Human); CVCL_3768
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vivo Model: NIH nude rat xenograft model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay

Disease Class: Melanoma [ICD-11: 2C30.0] [36]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Synonymous; p.K601K (c.1803A>G)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Melanoma [ICD-11: 2C30.0] [3]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Synonymous; p.L597L (c.1791A>T)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Melanoma [ICD-11: 2C30.0] [30]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.K601R (c.1802A>G)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Melanoma [ICD-11: 2C30.0] [33]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.L597R (c.1790T>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293H cells; Fetal kidney; Homo sapiens (Human); CVCL_ZK99
• Experiment for Molecule Alteration: Whole genome sequencing assay

Disease Class: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0] [37]

• Sensitive Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: IF-deletion; p.N486_P490delNVTAP (c.1457_1471del15)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Blood sample; N.A.

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [38]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.F247L (c.739T>C)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMLER cells; Breast; Homo sapiens (Human); CVCL_DG85
• In Vivo Model: Athymic mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay; Immunofluorescence assay; qPCR
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Reseachers identified an oncogenic mutation, F247L, whose expression robustly activated the MAPK pathway and sensitized cells to BRAF and MEK inhibitors.

Disease Class: Melanoma [ICD-11: 2C30.0] [6]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Experimental Note: Identified from the Human Clinical Data

Trametinib/Dabrafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Melanoma [ICD-11: 2C30.0] [39]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Trametinib/Dabrafenib
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; N.A.
• Experiment for Drug Resistance: Tumor evaluation assay

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Thyroid gland cancer [ICD-11: 2D10.0] [40]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: Trametinib/Dabrafenib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

Vemurafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Papillary thyroid carcinoma [ICD-11: 2D10.1] [41]

• Resistant Disease: Papillary thyroid carcinoma [ICD-11: 2D10.1]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Missense mutation; p.V600E
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Low throughput experiment assay
• Mechanism Description: BRAFV600E is the most common mutation in PTC, occurring in about 60% of PTC tumors, and has been described as a clonal event since it occurs in the majority of tumor cells. BRAFV600E PTC exhibits primary resistance to RAI treatment, higher rates of tumor recurrence and metastases, and lower survival rates. Remarkably, the BRAFV600E mutation not only promotes thyroid tumor cell proliferation, adhesion, migration and invasion, but also up-regulates epigenetic pathways that silence expression of the sodium/iodide symporter. This blocks iodide uptake, which may be one cause of primary resistance to RAI. Present in other cancers, including 40-70% of malignant melanomas and 10% of colorectal cancers, BRAFV600E positive tumors provide one important case study for the evolution of drug resistance.

Disease Class: Melanoma [ICD-11: 2C30.0] [42]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Structural variation; Copy number gain
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall or disease-free survival assay
• Mechanism Description: Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [43]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ERK1/2/MEK activation signaling pathway|hsa04210); Regulation; N.A.
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: PI3K signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS signaling pathway; Activation; hsa04014
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Western blot analysis; GTPase assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR204-5p and miR211-5p contribute to BRAF inhibitor resistance in melanoma. MTT assays revealed a moderate but consistent increase in resistance to VMF in cells overexpressing miR211-5p or miR204-5p. Joint overexpression of miR204-5p and miR211-5p durably stimulated Ras and MAPk upregulation. Resistance to BRAFi in melanoma involves genetic alterations that lead to reactivation of the MAPk pathway or activation of PI3-k/AkT signalling.

Clinical Trial Drug(s) 18 drug(s) in total

Cobimetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lymphatic system cancer [ICD-11: 2E81.1] [44]

• Sensitive Disease: Lymphatic system cancer [ICD-11: 2E81.1]
• Sensitive Drug: Cobimetinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Whole exome sequencing; Targeted Exon Sequencing
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [45]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Cobimetinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Cobimetinib by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [44]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Cobimetinib
• Molecule Alteration: Complex-indel; p.N486_T491delinsK (c.1458_1472del15)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Whole exome sequencing; Targeted Exon Sequencing
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Disease Class: Lymphatic system cancer [ICD-11: 2E81.1] [44]

• Sensitive Disease: Lymphatic system cancer [ICD-11: 2E81.1]
• Sensitive Drug: Cobimetinib
• Molecule Alteration: Complex-indel; p.N486_T491delinsK (c.1458_1472del15)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Whole exome sequencing; Targeted Exon Sequencing
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Disease Class: Melanoma [ICD-11: 2C30.0] [3]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Cobimetinib
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Skin sample; N.A.
• In Vivo Model: Mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Crystal violet staining assay

Ganetespib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [46]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Ganetespib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-1 cell proliferation assay

Refametinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [47]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Refametinib
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The missense mutation p.V600X (c.1798_1799) in gene BRAF cause the resistance of Refametinib by aberration of the drug's therapeutic target

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [48]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Refametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• 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: BxPc3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vivo Model: Female athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Biochemical kinase assays
• Experiment for Drug Resistance: CellTiter 96 Aqueous One assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Refametinib by unusual activation of pro-survival pathway

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [48]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Refametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• 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: BxPc3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vivo Model: Female athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Biochemical kinase assays
• Experiment for Drug Resistance: CellTiter 96 Aqueous One assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Refametinib by unusual activation of pro-survival pathway

Selumetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01] [49]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Sensitive Drug: Selumetinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Disease Class: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01] [49]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Sensitive Drug: Selumetinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Disease Class: Thyroid gland cancer [ICD-11: 2D10.0] [50]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: Selumetinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BRAF/MEK/MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: BCPAP cells; Thyroid; Homo sapiens (Human); CVCL_0153
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: CAL62 cells; Thyroid gland; Homo sapiens (Human); CVCL_1112
• In Vivo Model: Athymic nude mouse PDX xenografts model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay; Immunoprecipitation assy
• Experiment for Drug Resistance: SRB staining assay; Promega assay
• Mechanism Description: Activation of the Mitogen Activated Protein (MAP) Kinase pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcome acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-Src gatekeeper mutation and MAP Kinase pathway signaling play important roles in promoting resistance to the Src inhibitor, dasatinib.

Vemurafenib/Cobimetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Melanoma [ICD-11: 2C30.0] [6]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Vemurafenib/Cobimetinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Disease Class: Melanoma [ICD-11: 2C30.0] [10]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Vemurafenib/Cobimetinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Disease Class: Melanoma [ICD-11: 2C30.0] [51]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Vemurafenib/Cobimetinib
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Melanoma [ICD-11: 2C30.0] [6]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Vemurafenib/Cobimetinib
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Experimental Note: Identified from the Human Clinical Data

E6201

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [52]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: E6201
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: G-361 cells; Skin; Homo sapiens (Human); CVCL_1220
• In Vitro Model: MDA-MB-435s cells; Breast; Homo sapiens (Human); CVCL_0622
• In Vitro Model: SEKI cells; Skin; Homo sapiens (Human); CVCL_3162
• In Vitro Model: HMV-1 cells; Uterus; Homo sapiens (Human); CVCL_8233
• In Vitro Model: HMCB cells; Skin; Homo sapiens (Human); CVCL_3317
• In Vitro Model: CHL-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_1122
• Experiment for Molecule Alteration: Western blot analysis; Immunohistochemistry assay
• Experiment for Drug Resistance: WST-8 assay

Pictilisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [53]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Pictilisib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ICH assay
• Experiment for Drug Resistance: Plasma level assay; Electrochemiluminescense assay

Pimasertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [54]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Pimasertib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• 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: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vivo Model: Female balb/c athymic (nu+/nu+) mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Pimasertib by aberration of the drug's therapeutic target

PLX8394

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [55]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: PLX8394
• Molecule Alteration: Missense mutation; p.G469A (c.1406G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC364 cells; Lung; Homo sapiens (Human); CVCL_5134
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vitro Model: H2087 cells; Lymph node; Homo sapiens (Human); CVCL_1524
• In Vitro Model: H1755 cells; Liver; Homo sapiens (Human); CVCL_1492
• In Vitro Model: H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: H1437 cells; Pleural effusion; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CAL-12T cells; Lung; Homo sapiens (Human); CVCL_1105
• In Vivo Model: SCID beige mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: PLX8394 was effective against treatment-naive BRAF-mutant LAs and those with acquired vemurafenib resistance caused by an alternatively spliced, truncated BRAFV600E that promotes vemurafenib-insensitive MAPK pathway signaling. Acquired PLX8394 resistance occurs via EGFR-mediated RAS-mTOR signaling and is prevented by upfront combination therapy with PLX8394 and either an EGFR or mTOR inhibitor.

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [56]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PLX8394
• Molecule Alteration: Synonymous; p.K601K (c.1803A>G)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [56]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PLX8394
• Molecule Alteration: Synonymous; p.G464G (c.1392A>T)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [56]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PLX8394
• Molecule Alteration: Missense mutation; p.G469R (c.1405G>A)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [56]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PLX8394
• Molecule Alteration: Missense mutation; p.G469A (c.1406G>C)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [56]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PLX8394
• Molecule Alteration: Missense mutation; p.G469V (c.1406G>T)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [56]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PLX8394
• Molecule Alteration: Synonymous; p.L597L (c.1791A>T)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [55]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: PLX8394
• Molecule Alteration: Missense mutation; p.G466V (c.1397G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC364 cells; Lung; Homo sapiens (Human); CVCL_5134
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vitro Model: H2087 cells; Lymph node; Homo sapiens (Human); CVCL_1524
• In Vitro Model: H1755 cells; Liver; Homo sapiens (Human); CVCL_1492
• In Vitro Model: H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: H1437 cells; Pleural effusion; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: CAL-12T cells; Lung; Homo sapiens (Human); CVCL_1105
• In Vivo Model: SCID beige mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: PLX8394 was effective against treatment-naive BRAF-mutant LAs and those with acquired vemurafenib resistance caused by an alternatively spliced, truncated BRAFV600E that promotes vemurafenib-insensitive MAPK pathway signaling. Acquired PLX8394 resistance occurs via EGFR-mediated RAS-mTOR signaling and is prevented by upfront combination therapy with PLX8394 and either an EGFR or mTOR inhibitor.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [57]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PLX8394
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PRT cells; Brain; Homo sapiens (Human); CVCL_7207
• In Vitro Model: 1205Lu cells; Skin; Homo sapiens (Human); CVCL_5239
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; AlamarBlue assay; Colony growth assay

RAF-265

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [58]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: RAF-265
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: BRAF kinase assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of RAF-265 by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [59]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: RAF-265
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; N.A.

RO-5126766 free base

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Thyroid gland cancer [ICD-11: 2D10.0] [60]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: RO-5126766 free base
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ERK signaling pathway; Inhibition; hsa04210

Disease Class: Melanoma [ICD-11: 2C30.0] [61]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: RO-5126766 free base
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: RT-4 cells; Urinary bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: RT-4 cells; Urinary bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: UM-UC-14 cells; Kidney; Homo sapiens (Human); CVCL_2747
• In Vitro Model: SUM-52PE cells; Pleural effusion; Homo sapiens (Human); CVCL_3425
• In Vitro Model: NCI-H1581 cells; Lung; Homo sapiens (Human); CVCL_1479
• In Vitro Model: MFE296 cells; Endometrium; Homo sapiens (Human); CVCL_1406
• In Vitro Model: MFE280 cells; Endometrium; Homo sapiens (Human); CVCL_1405
• In Vitro Model: KMS-11 cells; Pleural effusion; Homo sapiens (Human); CVCL_2989
• In Vitro Model: HSC-39 cells; Ascites; Homo sapiens (Human); CVCL_A385
• In Vitro Model: DMS-114 cells; Lung; Homo sapiens (Human); CVCL_1174
• In Vitro Model: AN3 CA cells; Endometrium; Homo sapiens (Human); CVCL_0028
• In Vitro Model: UM-UC-14 cells; Kidney; Homo sapiens (Human); CVCL_2747
• In Vitro Model: KATO-III cells; Pleural effusion; Homo sapiens (Human); CVCL_0371
• In Vitro Model: AN3 CA cells; Endometrium; Homo sapiens (Human); CVCL_0028
• Experiment for Molecule Alteration: Microarray assay; Western blot analysis
• Experiment for Drug Resistance: CCK-8 assay

Ulixertinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01] [62]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Sensitive Drug: Ulixertinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Ulixertinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [63]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Ulixertinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• 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: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: G-361 cells; Skin; Homo sapiens (Human); CVCL_1220
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vitro Model: AN3CA cells; Ovary; Homo sapiens (Human); CVCL_0028
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vivo Model: Athymic nude mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Standard coupled-enzyme assay

Disease Class: Melanoma [ICD-11: 2C30.0] [63]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Ulixertinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• 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: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: G-361 cells; Skin; Homo sapiens (Human); CVCL_1220
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vitro Model: AN3CA cells; Ovary; Homo sapiens (Human); CVCL_0028
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vivo Model: Athymic nude mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Standard coupled-enzyme assay

Disease Class: Head and neck cancer [ICD-11: 2D42.0] [62]

• Sensitive Disease: Head and neck cancer [ICD-11: 2D42.0]
• Sensitive Drug: Ulixertinib
• Molecule Alteration: Missense mutation; p.G469A (c.1406G>C)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [62]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Ulixertinib
• Molecule Alteration: Missense mutation; p.L597Q (c.1790T>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

Disease Class: Gallbladder cancer [ICD-11: 2C13.0] [62]

• Sensitive Disease: Gallbladder cancer [ICD-11: 2C13.0]
• Sensitive Drug: Ulixertinib
• Molecule Alteration: Missense mutation; p.L485W (c.1454T>G)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Small intestine carcinoma [ICD-11: 2B80.20] [62]

• Sensitive Disease: Small intestine carcinoma [ICD-11: 2B80.20]
• Sensitive Drug: Ulixertinib
• Molecule Alteration: Missense mutation; p.G469A (c.1406G>C)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

Agerafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Colon cancer [ICD-11: 2B90.1] [64]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Sensitive Drug: Agerafenib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Agerafenib by aberration of the drug's therapeutic target

Disease Class: Melanoma [ICD-11: 2C30.0] [64]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Agerafenib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Agerafenib 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: Melanoma [ICD-11: 2C30.0] [65]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Lifirafenib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• 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 blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Tumor volume measurement assay

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [65]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Lifirafenib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• 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 blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Tumor volume measurement assay

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [65]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Lifirafenib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• 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 blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Tumor volume measurement assay

BI-847325

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [66]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: BI-847325
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM793 cells; N.A.; Homo sapiens (Human); CVCL_8787/CVCL_5414
• In Vitro Model: WM39 cells; Skin; Homo sapiens (Human); CVCL_2240
• In Vitro Model: WM164 cells; Skin; Homo sapiens (Human); CVCL_7928
• In Vitro Model: RPMI-7951 cells; Lymph node; Homo sapiens (Human); CVCL_1666
• In Vitro Model: 1205Lu cells; Skin; Homo sapiens (Human); CVCL_5239
• In Vivo Model: BALB SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; qPCR; Proteasome-Glo Chymotrypsin-like cell-based assay
• Experiment for Drug Resistance: Alamar blue assay; Colony formation assay

LY3009120

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Hematologic Cancer [ICD-11: MG24.Y] [32]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: LY3009120
• Molecule Alteration: Missense mutation; p.K601N (c.1803A>C)
• Experimental Note: Revealed Based on the Cell Line Data
• 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: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: OV-90 cells; Ascites; Homo sapiens (Human); CVCL_3768
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vivo Model: NIH nude rat xenograft model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [32]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: LY3009120
• Molecule Alteration: Complex-indel; p.L485_P490delinsY (c.1453_1470delinsTAT)
• Experimental Note: Revealed Based on the Cell Line Data
• 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: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: OV-90 cells; Ascites; Homo sapiens (Human); CVCL_3768
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vivo Model: NIH nude rat xenograft model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay

Disease Class: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0] [32]

• Sensitive Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Sensitive Drug: LY3009120
• Molecule Alteration: Complex-indel; p.V487_P492delinsA (c.1460_1474del15)
• Experimental Note: Revealed Based on the Cell Line Data
• 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: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: OV-90 cells; Ascites; Homo sapiens (Human); CVCL_3768
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vivo Model: NIH nude rat xenograft model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [67]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: LY3009120
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM2664 cells; Skin; Homo sapiens (Human); CVCL_2765
• In Vitro Model: SkMEL 30 cells; Skin; Homo sapiens (Human); CVCL_0039
• In Vitro Model: SkMEL 2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: SH4 cells; Skin; Mus musculus (Mouse); CVCL_7702
• In Vitro Model: MEXF-535 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1792 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: MEXF-1341 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: M14 cells; Hypodermis; Homo sapiens (Human); CVCL_1395
• In Vitro Model: GAK cells; Lnguinal lymph node; Homo sapiens (Human); CVCL_1225
• In Vitro Model: Colo829 cells; Skin; Homo sapiens (Human); CVCL_1137
• In Vivo Model: Female NIH nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Crystallization assay; X-ray data collection and structure determination assay
• Experiment for Drug Resistance: CellTiter-Glo assay; Enzymatic kinase assay

Disease Class: Melanoma [ICD-11: 2C30.0] [3]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: LY3009120
• Molecule Alteration: Missense mutation; p.L597S (c.1789_1790delCTinsTC)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Skin sample; N.A.
• In Vivo Model: Mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Crystal violet staining assay

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [32]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: LY3009120
• Molecule Alteration: IF-deletion; p.L485_P490delLNVTAP (c.1453_1470del18)
• Experimental Note: Revealed Based on the Cell Line Data
• 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: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: OV-90 cells; Ascites; Homo sapiens (Human); CVCL_3768
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vivo Model: NIH nude rat xenograft model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay

Disease Class: Ovarian cancer [ICD-11: 2C73.0] [32]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: LY3009120
• Molecule Alteration: IF-deletion; p.N486_P490delNVTAP (c.1457_1471del15)
• Experimental Note: Revealed Based on the Cell Line Data
• 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: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: OV-90 cells; Ascites; Homo sapiens (Human); CVCL_3768
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vivo Model: NIH nude rat xenograft model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay

Omipalisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [68]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Omipalisib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Omipalisib by unusual activation of pro-survival pathway

Disease Class: Melanoma [ICD-11: 2C30.0] [68]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Omipalisib
• Molecule Alteration: Missense mutation; p.V600K (c.1798_1799delGTinsAA)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: The missense mutation p.V600K (c.1798_1799delGTinsAA) in gene BRAF cause the sensitivity of Omipalisib by unusual activation of pro-survival pathway

PLX4720

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01] [69]

• Resistant Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Resistant Drug: PLX4720
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: GBM cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Athymic mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Alamar blue proliferation assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Melanoma [ICD-11: 2C30.0] [70]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: PLX4720
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of PLX4720 by aberration of the drug's therapeutic target

Disease Class: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01] [71]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Sensitive Drug: PLX4720
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: HS683 cells; Brain; Homo sapiens (Human); CVCL_0844
• In Vitro Model: DBTRG-05MG cells; Brain; Homo sapiens (Human); CVCL_1169
• In Vitro Model: NMC-G1 cells; Brain; Homo sapiens (Human); CVCL_1608
• In Vitro Model: MO59J cells; Brain; Homo sapiens (Human); CVCL_0400
• In Vitro Model: LN405 cells; Brain; Homo sapiens (Human); CVCL_1378
• In Vitro Model: LN172 cells; N.A.; N.A.; N.A.
• In Vitro Model: KG1c cells; Brain; Homo sapiens (Human); CVCL_2971
• In Vitro Model: H4 cells; Brain; Homo sapiens (Human); CVCL_1239
• In Vitro Model: GMS10 cells; Brain; Homo sapiens (Human); CVCL_1233
• In Vitro Model: GAMG cells; Brain; Homo sapiens (Human); CVCL_1226
• In Vitro Model: CCF-STTG1 cells; Brain; Homo sapiens (Human); CVCL_1118
• In Vitro Model: AM-38 cells; Brain; Homo sapiens (Human); CVCL_1070
• In Vitro Model: 8MGBA cells; Brain; Homo sapiens (Human); CVCL_1052
• In Vitro Model: 42MGBA cells; Brain; Homo sapiens (Human); CVCL_1798
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: PLX4720 suppresses MEK-ERK phosphorylation and cell proliferation in MA cells containing BRAFV600E mutation.

Disease Class: Colon cancer [ICD-11: 2B90.1] [70]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Sensitive Drug: PLX4720
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of PLX4720 by aberration of the drug's therapeutic target

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [58]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PLX4720
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: BRAF kinase assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of PLX4720 by aberration of the drug's therapeutic target

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

RO4987655

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [61]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: RO4987655
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: RT-4 cells; Urinary bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: RT-4 cells; Urinary bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: UM-UC-14 cells; Kidney; Homo sapiens (Human); CVCL_2747
• In Vitro Model: SUM-52PE cells; Pleural effusion; Homo sapiens (Human); CVCL_3425
• In Vitro Model: NCI-H1581 cells; Lung; Homo sapiens (Human); CVCL_1479
• In Vitro Model: MFE296 cells; Endometrium; Homo sapiens (Human); CVCL_1406
• In Vitro Model: MFE280 cells; Endometrium; Homo sapiens (Human); CVCL_1405
• In Vitro Model: KMS-11 cells; Pleural effusion; Homo sapiens (Human); CVCL_2989
• In Vitro Model: HSC-39 cells; Ascites; Homo sapiens (Human); CVCL_A385
• In Vitro Model: DMS-114 cells; Lung; Homo sapiens (Human); CVCL_1174
• In Vitro Model: AN3 CA cells; Endometrium; Homo sapiens (Human); CVCL_0028
• In Vitro Model: UM-UC-14 cells; Kidney; Homo sapiens (Human); CVCL_2747
• In Vitro Model: KATO-III cells; Pleural effusion; Homo sapiens (Human); CVCL_0371
• In Vitro Model: AN3 CA cells; Endometrium; Homo sapiens (Human); CVCL_0028
• Experiment for Molecule Alteration: Microarray assay; Western blot analysis
• Experiment for Drug Resistance: CCK-8 assay

Disease Class: Melanoma [ICD-11: 2C30.0] [72]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: RO4987655
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1799)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; N.A.
• Experiment for Molecule Alteration: IHC assay; Tumor-DNA mutation analysis
• Experiment for Drug Resistance: Pharmacokinetics analysis; Tumor biopsies analysis

Preclinical Drug(s) 14 drug(s) in total

Alpelisib/Cetuximab/Encorafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [73]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Alpelisib/Cetuximab/Encorafenib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: WiDR cells; Colon; Homo sapiens (Human); CVCL_2760
• In Vitro Model: VACO432 cells; Colon; Homo sapiens (Human); CVCL_5402
• In Vitro Model: HROC87 cells; Colon; Homo sapiens (Human); CVCL_S854
• Experiment for Molecule Alteration: SDS-PAGE assay; Western blot analysis; chemiluminescent detection assay
• Experiment for Drug Resistance: CellTiter-Glo luminescent assay; CellTox green assay
• Mechanism Description: Resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway.

BI-2536

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01] [69]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Sensitive Drug: BI-2536
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: GBM cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Athymic mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Alamar blue proliferation assay

BI-69A11

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [74]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: BI-69A11
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data

Buparlisib/Vemurafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Melanoma [ICD-11: 2C30.0] [75]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Buparlisib/Vemurafenib
• Molecule Alteration: Missense mutation; p.V600X (c.1798_1800)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Melanoma cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: WM cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: SK cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Fluorescent microscopy assay; Apoptosis analysis

CCT196969

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [76]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: CCT196969
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Disease Class: Melanoma [ICD-11: 2C30.0] [77]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: CCT196969
• Molecule Alteration: Missense mutation; p.V600D (c.1799_1800delTGinsAC)
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [76]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: CCT196969
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vivo Model: Female xenograft nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Sanger Sequencing
• Experiment for Drug Resistance: CellTiter-Glo assay; Tumor volume measurement assay

CCT241161

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [76]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: CCT241161
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Disease Class: Melanoma [ICD-11: 2C30.0] [77]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: CCT241161
• Molecule Alteration: Missense mutation; p.V600D (c.1799_1800delTGinsAC)
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [76]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: CCT241161
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vivo Model: Female xenograft nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Sanger Sequencing
• Experiment for Drug Resistance: CellTiter-Glo assay; Tumor volume measurement assay

Cediranib/PLX4720

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [78]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Cediranib/PLX4720
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: WM451 cells; Skin; Homo sapiens (Human); CVCL_6357
• In Vivo Model: Nu/Nu(ISTMel1) mouse xenograft model; NSG (RPMI7951) female mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Immunohistochemistry assay
• Experiment for Drug Resistance: CellTiter-Glo assay

Cetuximab/Selumetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [73]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Cetuximab/Selumetinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: WiDR cells; Colon; Homo sapiens (Human); CVCL_2760
• In Vitro Model: VACO432 cells; Colon; Homo sapiens (Human); CVCL_5402
• In Vitro Model: HROC87 cells; Colon; Homo sapiens (Human); CVCL_S854
• Experiment for Molecule Alteration: SDS-PAGE assay; Western blot analysis; chemiluminescent detection assay
• Experiment for Drug Resistance: CellTiter-Glo luminescent assay; CellTox green assay
• Mechanism Description: Resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway.

CLM3

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Thyroid gland cancer [ICD-11: 2D10.0] [79]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: CLM3
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 8305C cells; Thyroid; Homo sapiens (Human); CVCL_1053
• In Vivo Model: Male CD nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Human cyclin D1 ELISA assay
• Experiment for Drug Resistance: WST-1 assay; Cell counting assay; Hoechst uptake assay; Annexin V binding assay

Dasatinib/SCH772984

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Thyroid gland cancer [ICD-11: 2D10.0] [50]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: Dasatinib/SCH772984
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BRAF/MEK/MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: BCPAP cells; Thyroid; Homo sapiens (Human); CVCL_0153
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: CAL62 cells; Thyroid gland; Homo sapiens (Human); CVCL_1112
• In Vivo Model: Athymic nude mouse PDX xenografts model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay; Immunoprecipitation assy
• Experiment for Drug Resistance: SRB staining assay; Promega assay
• Mechanism Description: Activation of the Mitogen Activated Protein (MAP) Kinase pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcome acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-Src gatekeeper mutation and MAP Kinase pathway signaling play important roles in promoting resistance to the Src inhibitor, dasatinib.

Dasatinib/Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Thyroid gland cancer [ICD-11: 2D10.0] [50]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: Dasatinib/Trametinib
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BRAF/MEK/MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: BCPAP cells; Thyroid; Homo sapiens (Human); CVCL_0153
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: CAL62 cells; Thyroid gland; Homo sapiens (Human); CVCL_1112
• In Vivo Model: Athymic nude mouse PDX xenografts model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay; Immunoprecipitation assy
• Experiment for Drug Resistance: SRB staining assay; Promega assay
• Mechanism Description: Activation of the Mitogen Activated Protein (MAP) Kinase pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcome acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-Src gatekeeper mutation and MAP Kinase pathway signaling play important roles in promoting resistance to the Src inhibitor, dasatinib.

DEL-22379

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [80]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: DEL-22379
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vivo Model: Female athymic nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Caspase-Glo 3/7 luminogenic assay

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [80]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: DEL-22379
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vivo Model: Female athymic nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Caspase-Glo 3/7 luminogenic assay

DETD-35

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Melanoma [ICD-11: 2C30.0] [81]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: DETD-35
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375-R cells; Skin; Homo sapiens (Human); CVCL_6234
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Acquired resistance to?vemurafenib?(PLX4032) is a thorny issue in BRAFV600E?mutant?melanoma?therapy. Ferroptotic?programmed cell death?is a potential strategy for combating therapy-resistant cancers. This study uncovers the adaptation and abnormal upregulation of PUFAs and bioactive?oxylipin?metabolism in PLX4032 resistant melanoma cells. Phyto-sesquiterpene lactone, DET, and its derivative, DETD-35, induced?lipid?ROS?accumulation and triggered?ferroptotic cell death?in PLX4032 sensitive (A375) and resistant (A375-R) BRAFV600E?melanoma cells by reprogramming?glutathione?and primary metabolisms, lipid/oxylipin metabolism, and causing mitochondrial damage in which DETD-35 showed superior efficiency to DET.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [82]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: DETD-35
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: STAT3 signaling pathway; Inhibition; hsa04550
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: MeWo cells; Skin; Homo sapiens (Human); CVCL_0445
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: B16-F10 cells; Skin; Mus musculus (Mouse); CVCL_0159
• In Vitro Model: SkMEL2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: BRAF cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Immunohistochemistry analysis
• Experiment for Drug Resistance: MTT assay; Crystal violet staining assay; FACS assay
• Mechanism Description: DETD-35 overcame acquired vemurafenib resistance at least in part through deregulating MEK-ERK, Akt, and STAT3 signaling pathways and promoting apoptosis of cancer cells.

EBI-907

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [83]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: EBI-907
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: SW-480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: Colo-205 cells; Ascites; Homo sapiens (Human); CVCL_0218
• In Vitro Model: Calu-6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vivo Model: Nu/Nu Colo-205 xenograft mouse model; Nu/Nu A357 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay

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: 7.57E-67; Fold-change: 5.39E-01; Z-score: 1.14E+00
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.65E-01; Fold-change: 5.98E-01; Z-score: 5.07E-01
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.08E-03; Fold-change: 4.28E-01; Z-score: 1.30E+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: 1.11E-05; Fold-change: 1.65E+00; Z-score: 2.77E+00

Gastric cancer [ICD-11: 2B72]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Gastric tissue
• The Specified Disease: Gastric cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.50E-01; Fold-change: -1.65E-01; Z-score: -9.71E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 7.01E-02; Fold-change: -2.60E-01; Z-score: -6.67E-01

Colon cancer [ICD-11: 2B90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Colon
• The Specified Disease: Colon cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.77E-56; Fold-change: 7.22E-01; Z-score: 1.93E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 9.73E-04; Fold-change: 2.68E-01; Z-score: 4.52E-01

Pancreatic cancer [ICD-11: 2C10]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Pancreas
• The Specified Disease: Pancreatic cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.38E-01; Fold-change: 2.78E-01; Z-score: 4.97E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 9.83E-02; Fold-change: -5.28E-02; Z-score: -1.13E-01

Liver cancer [ICD-11: 2C12]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Liver
• The Specified Disease: Liver cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.47E-07; Fold-change: 4.55E-01; Z-score: 8.68E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.11E-05; Fold-change: 2.15E-01; Z-score: 3.87E-01
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 5.15E-01; Fold-change: -2.35E-03; Z-score: -9.39E-03

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: 6.30E-20; Fold-change: 5.74E-01; Z-score: 9.81E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.37E-19; Fold-change: 6.19E-01; Z-score: 1.12E+00

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: 1.19E-02; Fold-change: 4.45E-01; Z-score: 7.27E-01

Ovarian cancer [ICD-11: 2C73]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Ovary
• The Specified Disease: Ovarian cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.90E-02; Fold-change: 2.92E-01; Z-score: 5.18E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 6.19E-05; Fold-change: 5.48E-01; Z-score: 1.57E+00

Bladder cancer [ICD-11: 2C94]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Bladder tissue
• The Specified Disease: Bladder cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.48E-03; Fold-change: -6.98E-01; Z-score: -1.61E+00

Thyroid cancer [ICD-11: 2D10]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Thyroid
• The Specified Disease: Thyroid cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.00E-01; Fold-change: 9.92E-02; Z-score: 2.05E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 9.41E-01; Fold-change: -2.90E-02; Z-score: -6.20E-02

Head and neck cancer [ICD-11: 2D42]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Head and neck tissue
• The Specified Disease: Head and neck cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.14E-02; Fold-change: -1.35E-01; Z-score: -2.67E-01

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