Drug Information

Drug (ID: DG01513) and It's Reported Resistant Information

• Name: Regorafenib
• Synonyms: Regorafenib; 755037-03-7; BAY 73-4506; Stivarga; 4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide; Regorafenibum; Regorafenib (BAY 73-4506); BAY73-4506; UNII-24T2A1DOYB; 4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide; BAY-73-4506; Regorafenib-13C-d3; 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide; 24T2A1DOYB; CHEMBL1946170; CHEBI:68647; Stivarga (TN); 4-(4-(((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)amino)-3-fluorophenoxy)-n-methylpyridine-2-carboxamide; Regorafenib [USAN:INN]; Fluoro-Sorafenib; 4-(4-(((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl}amino)-3-fluorophenoxy)-N-methylpyridine-2-carboxamide; Regorafenib (USAN/INN); RegorafenibBAY73-4506; MLS006010303; C21H15ClF4N4O3; Regorafenib crystalline form I; SCHEMBL432230; Regorafenib,BAY 73-4506; GTPL5891; QCR-85; Bay-734506; DTXSID60226441; EX-A058; Regorafenib - BAY 73-4506; SYN1169; BCPP000352; HMS3654K16; HMS3672E15; AOB87754; BCP02105; BKD17855; ZINC6745272; BDBM50363397; MFCD16038047; NSC763932; NSC800865; s1178; AKOS015951107; AM81251; BAY 734506; BCP9000384; CCG-269571; CS-0170; DB08896; NSC-763932; NSC-800865; SB16819; NCGC00263138-01; NCGC00263138-13; NCGC00263138-19; 2-Pyridinecarboxamide,4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-3-fluorophenoxy]-N-methyl-; AC-25075; AC-31116; AS-16304; HY-10331; SMR004701370; FT-0674338; R0142; SW218097-2; cas:835621-07-3;Regorafenib hydrochloride; Regorafenib (BAY73-4506,Fluoro-Sorafenib); A25020; D10138; AB01565826_02; SR-01000941571; Q3891664; SR-01000941571-1; BRD-K16730910-001-02-4; 2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-3-fluorophenoxy]-N-methyl-; 4-[4-({[4-Chloro-3-(trifluoromethy)phenyl]carbamoyl}amino)-3-fluorophenoxy]-1-methylpyridine-2-carboxamide; 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide; 835621-08-4; Regorafenib;1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea
• Indication:
  In total 1 Indication(s)
  Metastatic colorectal cancer [ICD-11: 2D85]; Phase 2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (4 diseases)
  Colorectal cancer [ICD-11: 2B91]; [2]
  Gastrointestinal cancer [ICD-11: 2B5B]; [3]
  Mastocytosis [ICD-11: 2A21]; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [4]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Colorectal cancer [ICD-11: 2B91]; [5]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [6]
• Target: Proto-oncogene c-Ret (RET); RET_HUMAN; [1]
• Formula: 5
• IsoSMILES: CNC(=O)C1=NC=CC(=C1)OC2=CC(=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F)F
• InChI: InChI=1S/C21H15ClF4N4O3/c1-27-19(31)18-10-13(6-7-28-18)33-12-3-5-17(16(23)9-12)30-20(32)29-11-2-4-15(22)14(8-11)21(24,25)26/h2-10H,1H3,(H,27,31)(H2,29,30,32)
• InChIKey: FNHKPVJBJVTLMP-UHFFFAOYSA-N
• PubChem CID: 11167602
• ChEBI ID: CHEBI:68647
• VARIDT ID: DR1401
• INTEDE ID: DR00136
• DrugBank ID: DB08896

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Molecule Alteration: Missense mutation; p.D816V (c.2447A>T)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: EOL1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0258
• In Vitro Model: CHO-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [1]

• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: EOL1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0258
• In Vitro Model: CHO-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Molecule Alteration: IF-deletion; p.P551_E554delPMYE (c.1651_1662del12)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Molecule Alteration: Missense mutation; p.D816H (c.2446G>C)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [6]

• Molecule Alteration: Missense mutation; p.F53L (c.157T>C)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.F53L (c.157T>C) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [6]

• Molecule Alteration: Missense mutation; p.Q56P (c.167A>C)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.Q56P (c.167A>C) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [6]

• Molecule Alteration: Missense mutation; p.K57N (c.171G>C)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.K57N (c.171G>C) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [6]

• Molecule Alteration: Missense mutation; p.I111S (c.332T>G)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.I111S (c.332T>G) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [6]

• Molecule Alteration: Missense mutation; p.C121S (c.361T>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.C121S (c.361T>A) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [6]

• Molecule Alteration: Missense mutation; p.F129L (c.385T>C)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.F129L (c.385T>C) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway

Key Molecule: MAPK/ERK kinase 1 (MEK1) [6]

• Molecule Alteration: Missense mutation; p.V211D (c.632T>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The missense mutation p.V211D (c.632T>A) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Molecule Alteration: IF-deletion; p.P551_K558delPMYEVQWK (c.1650_1673del24)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Molecule Alteration: IF-deletion; p.W557_K558delWK (c.1669_1674delTGGAAG)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Molecule Alteration: Complex-indel; p.K558_558delinsNP (c.1672_1674delinsAACCCT)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Molecule Alteration: Missense mutation; p.V560D (c.1679T>A)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Mastocytosis [ICD-11: 2A21]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Molecule Alteration: Missense mutation; p.D816Y (c.2446G>T)
• Resistant Disease: Mast cell neoplasm [ICD-11: 2A21.1]
• Experimental Note: Identified from the Human Clinical Data

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Molecule Alteration: Missense mutation; p.V560G (c.1679T>G)
• Sensitive Disease: Mast cell neoplasm [ICD-11: 2A21.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: EOL1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0258
• In Vitro Model: CHO-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Acute myeloid leukemia [ICD-11: 2A60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Molecule Alteration: Missense mutation; p.N822K (c.2466T>G)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: EOL1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0258
• In Vitro Model: CHO-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Gastrointestinal cancer [ICD-11: 2B5B]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]

• Molecule Alteration: Other; .
• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• 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.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [7]

• Molecule Alteration: Missense mutation; p.T670I (c.2009C>T)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Molecule Alteration: Missense mutation; p.V560G (c.1679T>G)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [8]

• Molecule Alteration: IF-deletion; p.C788_N828 (c.2362_2484)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [8]

• Molecule Alteration: IF-deletion; p.R449_E514 (c.1345_1542)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [8]

• Molecule Alteration: IF-deletion; p.K550_G592 (c.1648_1776)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [8]

• Molecule Alteration: IF-deletion; p.P627_G664 (c.1879_1992)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [8]

• Molecule Alteration: IF-deletion; p.G664_C714 (c.1990_2142)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [9]

• Molecule Alteration: IF-deletion; p.K550_G592 (c.1648_1774)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [7]

• Molecule Alteration: Missense mutation; p.V654A (c.1961T>C)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Molecule Alteration: IF-deletion; p.K558_V559delKV (c.1672_1677delAAGGTT)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Molecule Alteration: Complex-indel; p.K558delinsNP (c.1674delinsTCCT)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Molecule Alteration: Missense mutation; p.V559D (c.1676T>A)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Molecule Alteration: IF-deletion; p.V560_L576del17 (c.1678_1728del51)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Molecule Alteration: Missense mutation; p.V560D (c.1679T>A)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: GIST-derived cells; N.A.; .; N.A.
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [3]

• Molecule Alteration: Missense mutation; p.D820Y (c.2458G>T)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Metastatic GI stromal tumor tissue; N.A.
• Mechanism Description: The missense mutation p.D820Y (c.2458G>T) in gene KIT cause the sensitivity of Regorafenib by aberration of the drug's therapeutic target

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [10]

• Molecule Alteration: IF-deletion; p.C814_S854 (c.2440_2562)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [11]

• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Gastrointestinal tract; N.A.
• Experiment for Drug Resistance: CT scan assay; MRI assay

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [10]

• Molecule Alteration: Missense mutation; p.Y894C
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [10]

• Molecule Alteration: IF-deletion; p.K552_G596 (c.1654_1788)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [10]

• Molecule Alteration: IF-deletion; p.P631_G668 (c.1891_2004)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [10]

• Molecule Alteration: Missense mutation; p.R748G (c.2242A>G)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [12]

• Molecule Alteration: Duplication; p.A502_Y503 (c.1504_1509)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: NOD/SCID mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Drug sensitivity test assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [13]

• Molecule Alteration: Missense mutation; p.K642E (c.1924A>G)
• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HUVEC cells; Endothelium; Homo sapiens (Human); N.A.
• In Vitro Model: HAoSMC cells; N.A.; .; N.A.
• In Vivo Model: Female athymic NCr nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTitre-Glo assay
• Mechanism Description: The missense mutation p.K642E (c.1924A>G) in gene KIT cause the sensitivity of Regorafenib by unusual activation of pro-survival pathway

Colorectal cancer [ICD-11: 2B91]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [14]

• Molecule Alteration: Missense mutation; p.R505C (c.1513C>T)
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: NCI-H508 cells; Colon; Homo sapiens (Human); CVCL_1564
• In Vitro Model: DiFi cells; Colon; Homo sapiens (Human); CVCL_6895
• In Vitro Model: VACO432 cells; Colon; Homo sapiens (Human); CVCL_5402
• In Vitro Model: PIK3CA-KO cells; N.A.; .; N.A.
• In Vitro Model: CCK-81 cells; N.A.; Homo sapiens (Human); CVCL_2873
• In Vitro Model: BRAF-KO cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: FBW7, an E3 ubiquitin ligase and a tumor suppressor frequently mutated in CRCs, contribute to resistance to targeted therapies. CRC cells containing FBW7 inactivating mutations are insensitive to clinically used multi-kinase inhibitors of RAS/RAF/MEK/ERK signaling, including regorafenib and sorafenib. In contrast, sensitivity to these agents is not affected by oncogenic mutations in KRAS, BRAF, PIK3CA, or p53. These cells are defective in apoptosis due to blocked degradation of Mcl-1, a pro-survival Bcl-2 family protein. Deleting FBW7 in FBW7-wild-type CRC cells abolishes Mcl-1 degradation and recapitulates the in vitro and in vivo drug resistance phenotypes of FBW7-mutant cells. CRC cells selected for regorafenib resistance have progressive enrichment of pre-existing FBW7 hotspot mutations, and are cross-resistant to other targeted drugs that induce Mcl-1 degradation. Furthermore, a selective Mcl-1 inhibitor restores regorafenib sensitivity in CRC cells with intrinsic or acquired resistance.

Key Molecule: VEGF-2 receptor (KDR) [2]

• Molecule Alteration: Missense mutation; p.L840F (c.2518C>T)
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: VEGF signaling pathway; Inhibition; hsa04370
• In Vitro Model: Colo-320 cells; Colon; Homo sapiens (Human); CVCL_1989
• In Vitro Model: MDST8 cells; Colon; Homo sapiens (Human); CVCL_2588
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: BEAMing assay; Western blotting analysis; immunofluorescence assay
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase KRas (KRAS) [5]

• Molecule Alteration: Missense mutation; p.G12S (c.34G>A)
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KRAS cells; N.A.; .; N.A.
• In Vitro Model: G12C cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: KRAS testing/KRAS quantification assay
• Experiment for Drug Resistance: MTT assay

Key Molecule: GTPase KRas (KRAS) [5]

• Molecule Alteration: Missense mutation; p.G12R (c.34G>C)
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KRAS cells; N.A.; .; N.A.
• In Vitro Model: G12C cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: KRAS testing/KRAS quantification assay
• Experiment for Drug Resistance: MTT assay

Key Molecule: GTPase KRas (KRAS) [5]

• Molecule Alteration: Missense mutation; p.G12C (c.34G>T)
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KRAS cells; N.A.; .; N.A.
• In Vitro Model: G12C cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: KRAS testing/KRAS quantification assay
• Experiment for Drug Resistance: MTT assay

Key Molecule: GTPase KRas (KRAS) [5]

• Molecule Alteration: Missense mutation; p.G12D (c.35G>A)
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KRAS cells; N.A.; .; N.A.
• In Vitro Model: G12C cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: KRAS testing/KRAS quantification assay
• Experiment for Drug Resistance: MTT assay

Key Molecule: GTPase KRas (KRAS) [5]

• Molecule Alteration: Missense mutation; p.G12A (c.35G>C)
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KRAS cells; N.A.; .; N.A.
• In Vitro Model: G12C cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: KRAS testing/KRAS quantification assay
• Experiment for Drug Resistance: MTT assay

Key Molecule: GTPase KRas (KRAS) [5]

• Molecule Alteration: Missense mutation; p.G12V (c.35G>T)
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KRAS cells; N.A.; .; N.A.
• In Vitro Model: G12C cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: KRAS testing/KRAS quantification assay
• Experiment for Drug Resistance: MTT assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: VEGF-2 receptor (KDR) [15]

• Molecule Alteration: Missense mutation; p.R961W (c.2881C>T)
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data

Thyroid cancer [ICD-11: 2D10]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [13]

• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HUVEC cells; Endothelium; Homo sapiens (Human); N.A.
• In Vitro Model: HAoSMC cells; N.A.; .; N.A.
• In Vivo Model: Female athymic NCr nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTitre-Glo assay
• Mechanism Description: The missense mutation p.C634W (c.1902C>G) in gene RET cause the sensitivity of Regorafenib by unusual activation of pro-survival pathway

References

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• Ref 8: U.S. Food and Drug Administration.
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• Ref 10: National Comprehensive Cancer Network.
• Ref 11: Regorafenib treatment for advanced, refractory gastrointestinal stromal tumor: a report of the UK managed access programClin Sarcoma Res. 2014 Dec 4;4:17. doi: 10.1186/2045-3329-4-17. eCollection 2014.
• Ref 12: Establishment and characterization of patient-derived xenograft models of gastrointestinal stromal tumor resistant to standard tyrosine kinase inhibitorsOncotarget. 2017 Sep 11;8(44):76712-76721. doi: 10.18632/oncotarget.20816. eCollection 2017 Sep 29.
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• Ref 15: KDR Mutation as a Novel Predictive Biomarker of Exceptional Response to Regorafenib in Metastatic Colorectal CancerCureus. 2016 Feb 3;8(2):e478. doi: 10.7759/cureus.478.