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 (5 diseases)
  Colorectal cancer [ICD-11: 2B91]; [2]
  Gastrointestinal cancer [ICD-11: 2B5B]; [3]
  Liver cancer [ICD-11: 2C12]; [4]
  Mastocytosis [ICD-11: 2A21]; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [5]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (3 diseases)
  Colorectal cancer [ICD-11: 2B91]; [6]
  Liver cancer [ICD-11: 2C12]; [4]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [7]
• 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

  MRAP: Metabolic Reprogramming via Altered Pathways

  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]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.D816V (c.2447A>T)
• 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); CVCL_0291
• 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) [5]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: IF-deletion; p.P551_E554delPMYE (c.1651_1662del12)
• 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; Gastric; Homo sapiens (Human); CVCL_4976
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [5]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.D816H (c.2446G>C)
• 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; Gastric; Homo sapiens (Human); CVCL_4976
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

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

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• 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); CVCL_0291
• 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

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [7]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.C121S (c.361T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.70 Å; PDB: 7B7R
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.01 Å; PDB: 7F2X

RMSD: 2.36; TM score: 0.87257; Amino acid change: C121S

• 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) [7]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.F53L (c.157T>C)
• 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) [7]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.Q56P (c.167A>C)
• 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) [7]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.K57N (c.171G>C)
• 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) [7]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.I111S (c.332T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: 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) [7]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.F129L (c.385T>C)
• 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) [7]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.V211D (c.632T>A)
• 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) [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: IF-deletion; p.P551_K558delPMYEVQWK (c.1650_1673del24)
• 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; Gastric; Homo sapiens (Human); CVCL_4976
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: IF-deletion; p.W557_K558delWK (c.1669_1674delTGGAAG)
• 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; Gastric; Homo sapiens (Human); CVCL_4976
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Complex-indel; p.K558_558delinsNP (c.1672_1674delinsAACCCT)
• 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; Gastric; Homo sapiens (Human); CVCL_4976
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.V560D (c.1679T>A)
• 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; Gastric; Homo sapiens (Human); CVCL_4976
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot 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]

• Resistant Disease: Mast cell neoplasm [ICD-11: 2A21.1]
• Molecule Alteration: Missense mutation; p.D816Y (c.2446G>T)
• 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]

• Sensitive Disease: Mast cell neoplasm [ICD-11: 2A21.1]
• Molecule Alteration: Missense mutation; p.V560G (c.1679T>G)
• 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); CVCL_0291
• 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]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.N822K (c.2466T>G)
• 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); CVCL_0291
• 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]

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

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) [8]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.T670I (c.2009C>T)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.25 Å; PDB: 6HH1
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.40 Å; PDB: 8PQG

RMSD: 1.88; TM score: 0.9084; Amino acid change: T670I

• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [5]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.V560G (c.1679T>G)
• 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; Gastric; Homo sapiens (Human); CVCL_4976
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

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

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

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

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

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

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

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

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

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

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

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [10]

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

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

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

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [5]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.K558_V559delKV (c.1672_1677delAAGGTT)
• 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; Gastric; Homo sapiens (Human); CVCL_4976
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [5]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Complex-indel; p.K558delinsNP (c.1674delinsTCCT)
• 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; Gastric; Homo sapiens (Human); CVCL_4976
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [5]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.V559D (c.1676T>A)
• 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; Gastric; Homo sapiens (Human); CVCL_4976
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [5]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: IF-deletion; p.V560_L576del17 (c.1678_1728del51)
• 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; Gastric; Homo sapiens (Human); CVCL_4976
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [5]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.V560D (c.1679T>A)
• 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; Gastric; Homo sapiens (Human); CVCL_4976
• In Vivo Model: Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Crystallography assay
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

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

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.D820Y (c.2458G>T)
• 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) [11]

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

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [12]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• 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) [11]

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

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

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

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

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

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

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.R748G (c.2242A>G)
• 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) [13]

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

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [14]

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Missense mutation; p.K642E (c.1924A>G)
• 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.; N.A.
• In Vivo Model: Female athymic NCr nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot 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) [15]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.R505C (c.1513C>T)
• 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.; 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 blot 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]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.L840F (c.2518C>T)
• 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 blot 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) [6]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.G12V (c.35G>T)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.98 Å; PDB: 7SCW
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.96 Å; PDB: 7SCX

RMSD: 0.47; TM score: 0.99104; Amino acid change: G12V

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KRAS cells; N.A.; N.A.; N.A.
• In Vitro Model: G12C cells; N.A.; N.A.; N.A.
• Experiment for Molecule Alteration: KRAS testing/KRAS quantification assay
• Experiment for Drug Resistance: MTT assay

Key Molecule: GTPase KRas (KRAS) [6]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.G12R (c.34G>C)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.40 Å; PDB: 6VJJ
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.50 Å; PDB: 6CU6

RMSD: 1.17; TM score: 0.95613; Amino acid change: G12R

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KRAS cells; N.A.; N.A.; N.A.
• In Vitro Model: G12C cells; N.A.; N.A.; N.A.
• Experiment for Molecule Alteration: KRAS testing/KRAS quantification assay
• Experiment for Drug Resistance: MTT assay

Key Molecule: GTPase KRas (KRAS) [6]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.G12A (c.35G>C)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.40 Å; PDB: 6VJJ
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.45 Å; PDB: 8TBJ

RMSD: 1.06; TM score: 0.96454; Amino acid change: G12A

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KRAS cells; N.A.; N.A.; N.A.
• In Vitro Model: G12C cells; N.A.; N.A.; N.A.
• Experiment for Molecule Alteration: KRAS testing/KRAS quantification assay
• Experiment for Drug Resistance: MTT assay

Key Molecule: GTPase KRas (KRAS) [6]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.G12C (c.34G>T)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.40 Å; PDB: 6VJJ
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.60 Å; PDB: 8JGD

RMSD: 1.55; TM score: 0.93157; Amino acid change: G12C

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KRAS cells; N.A.; N.A.; N.A.
• In Vitro Model: G12C cells; N.A.; N.A.; N.A.
• Experiment for Molecule Alteration: KRAS testing/KRAS quantification assay
• Experiment for Drug Resistance: MTT assay

Key Molecule: GTPase KRas (KRAS) [6]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.G12S (c.34G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.24 Å; PDB: 4OBE
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.71 Å; PDB: 7TLK

RMSD: 1.85; TM score: 0.93473; Amino acid change: G12S

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KRAS cells; N.A.; N.A.; N.A.
• In Vitro Model: G12C cells; N.A.; N.A.; N.A.
• Experiment for Molecule Alteration: KRAS testing/KRAS quantification assay
• Experiment for Drug Resistance: MTT assay

Key Molecule: GTPase KRas (KRAS) [6]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.G12D (c.35G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.40 Å; PDB: 6VJJ
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.10 Å; PDB: 8JHL

RMSD: 1.55; TM score: 0.9318; Amino acid change: G12D

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KRAS cells; N.A.; N.A.; N.A.
• In Vitro Model: G12C cells; N.A.; 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) [16]

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

Liver cancer [ICD-11: 2C12]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [4]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell prognosis assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Key Molecule: Long intergenic non-protein coding RNA (HNF4A-AS1) [17]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Huh7 cells; Kidney; Homo sapiens (Human); CVCL_U442
• In Vitro Model: Huh7-R cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: Gene set enrichment analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC.

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [4]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vitro Model: L-02 hepatic non-tumor cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [4]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice, MHCC97-H cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [18]

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

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [18]

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

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) [14]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• 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.; N.A.
• In Vivo Model: Female athymic NCr nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot 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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