Drug Information

Drug (ID: DG00617) and It's Reported Resistant Information

• Name: Cabozantinib
• Synonyms: Cabozantinib; 849217-68-1; Cometriq; XL184; XL-184; BMS-907351; XL 184; BMS 907351; Cabozantinib (XL184, BMS-907351); UNII-1C39JW444G; CHEBI:72317; XL-184 free base; BMS907351; 1C39JW444G; MFCD20926324; N'-[4-[(6,7-DIMETHOXY-4-QUINOLINYL)OXY]PHENYL]-N-(4-FLUOROPHENYL)-1,1-CYCLOPROPANEDICARBOXAMIDE; Cabometyx (TN); Cometriq (TN); 1-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide; C28H24FN3O5; N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide; N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide; XL184 cpd; Cabozantinib [USAN:INN]; Carbozantinib; XL184 free base; Cabozantinib (USAN); Cabozantinib (free base); SCHEMBL360795; GTPL5887; Cabozantinib (BMS-907351); CHEMBL2105717; DTXSID10233968; EX-A075; QCR-122; SYN1138; XL184 free base - Cabozantinib; BCPP000308; BMS-907351 FREE BASE; HMS3654G06; XL-184 free base (Cabozantinib); AOB87755; BCP02591; 849217-68-1 (free base); BDBM50021574; NSC761068; NSC800066; s1119; ZINC70466416; AKOS025142112; BCP9000470; CCG-264678; CS-0278; DB08875; NSC-761068; NSC-800066; SB20062; XL-184 (Cabozantinib,BMS907351); XL-184,Cabozantinib, BMS-907351; NCGC00263164-01; NCGC00263164-14; NCGC00263164-17; 1,1-Cyclopropanedicarboxamide, N'-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N-(4-fluorophenyl)-; 1,1-Cyclopropanedicarboxamide,N-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N'-(4-fluorophenyl)-; AC-25082; AS-16277; HY-13016; n-(4-((6,7-dimethoxy-4-quinolinyl)oxy)phenyl)-n'-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide; SY097158; DB-023624; FT-0664184; SW218093-3; X7477; D10062; AB01565831_02; Q795057; SR-01000941569; J-523016; SR-01000941569-1; BRD-K51544265-001-01-8; 1,1-Cyclopropanedicarboxamide, N'-(4-((6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N-(4- fluorophenyl)-; cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide; cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide; N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4 fluorophenyl)cyclopropane-1,1-dicarboxamide; N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide; N-[4-[(6,7-Dimethoxy-4-quinolinyl)oxy]phenyl]-N-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide; N-[4-[(6,7-Dimethoxyquinolin-4-yl)oxy]phenyl]-N inverted exclamation mark -(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
• Indication:
  In total 3 Indication(s)
  Ovarian cancer [ICD-11: 2C73]; Approved; [1]
  Thyroid cancer [ICD-11: 2D10]; Approved; [1]
  Thyroid cancer [ICD-11: 2D10]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (4 diseases)
  Kidney cancer [ICD-11: 2C90]; [2]
  Liver cancer [ICD-11: 2C12]; [3]
  Lung cancer [ICD-11: 2C25]; [4]
  Multiple endocrine neoplasia [ICD-11: 2F7A]; [1]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Liver cancer [ICD-11: 2C12]; [3]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [5]
• Target: Proto-oncogene c-Met (MET); MET_HUMAN; [2]
• Target: Vascular endothelial growth factor receptor 2 (KDR); VGFR2_HUMAN; [2]
• Formula: C28H24FN3O5
• IsoSMILES: COC1=CC2=C(C=CN=C2C=C1OC)OC3=CC=C(C=C3)NC(=O)C4(CC4)C(=O)NC5=CC=C(C=C5)F
• InChI: 1S/C28H24FN3O5/c1-35-24-15-21-22(16-25(24)36-2)30-14-11-23(21)37-20-9-7-19(8-10-20)32-27(34)28(12-13-28)26(33)31-18-5-3-17(29)4-6-18/h3-11,14-16H,12-13H2,1-2H3,(H,31,33)(H,32,34)
• InChIKey: ONIQOQHATWINJY-UHFFFAOYSA-N
• PubChem CID: 25102847
• ChEBI ID: CHEBI:72317
• TTD Drug ID: D0IQ6P
• INTEDE ID: DR0254
• DrugBank ID: DB08875

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

  RTDM: Regulation by the Disease Microenvironment

  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

Unusual Activation of Pro-survival Pathway (UAPP)

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.D816V (c.2447A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 32D cells; Bone marrow; Homo sapiens (Human); CVCL_0118
• In Vivo Model: Female Balb/cA-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.D816V (c.2447A>T) in gene KIT cause the resistance of Cabozantinib by aberration of the drug's therapeutic target

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Hepatocyte growth factor receptor (MET) [6]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.Y1003F (c.3008A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: WEHI-3 cells; Peripheral blood; Mus musculus (Mouse); CVCL_3622
• In Vitro Model: Hs746T cells; Skeletal muscle; Homo sapiens (Human); CVCL_0333
• In Vitro Model: Gp2-293 cells; Fetal kidney; Homo sapiens (Human); CVCL_WI48
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Hepatocyte growth factor receptor (MET) [6]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.D1010Y (c.3028G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: WEHI-3 cells; Peripheral blood; Mus musculus (Mouse); CVCL_3622
• In Vitro Model: Hs746T cells; Skeletal muscle; Homo sapiens (Human); CVCL_0333
• In Vitro Model: Gp2-293 cells; Fetal kidney; Homo sapiens (Human); CVCL_WI48
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Hepatocyte growth factor receptor (MET) [7]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.D1228V (c.3683A>T)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.71 Å; PDB: 5HNI
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.67 Å; PDB: 6SDC

RMSD: 1.85; TM score: 0.88477; Amino acid change: D1228V

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: There is a patient with metastatic NSCLC with MET-mediated resistance to EGFR TKI who responded to treatment with a type I MET inhibitor, savolitinib, given in combination with a third-generation EGFR inhibitor, osimertinib. The patient then developed acquired resistance mediated by a novel MET kinase domain mutation.

Key Molecule: Hepatocyte growth factor receptor (MET) [8]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.Y1230H (c.3688T>C)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.71 Å; PDB: 5HNI
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.97 Å; PDB: 5HLW

RMSD: 0.65; TM score: 0.96625; Amino acid change: Y1230H

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); CVCL_0594
• In Vivo Model: Athymic female mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: MET mutations Y1248H and D1246N are resistance mechanisms for type I MET-TKIs. NIH3T3 cells expressing either mutation showed resistance to both INC280 and crizotinib but not cabozantinib, indicating the potential of sequential use of MET inhibitors may lead to a more durable response.

Key Molecule: Hepatocyte growth factor receptor (MET) [8]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.D1228N (c.3682G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); CVCL_0594
• In Vivo Model: Athymic female mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: MET mutations Y1248H and D1246N are resistance mechanisms for type I MET-TKIs. NIH3T3 cells expressing either mutation showed resistance to both INC280 and crizotinib but not cabozantinib, indicating the potential of sequential use of MET inhibitors may lead to a more durable response.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [9]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.V299L (c.895G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ph+ALL cells; N.A.; N.A.; N.A.
• Mechanism Description: The missense mutation p.V299L (c.895G>C) in gene ABL1 cause the sensitivity of Cabozantinib by aberration of the drug's therapeutic target

Gastrointestinal cancer [ICD-11: 2B5B]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

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

• 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 Vitro Model: Clinical GIST specimens; N.A.
• In Vivo Model: NMRI mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: Cabozantinib inhibited the KIT signaling pathway in UZLX-GIST4 and -GIST2. In addition, compared with both control and imatinib, cabozantinib significantly reduced microvessel density in all models. Cabozantinib showed antitumor activity in GIST PDX models through inhibition of tumor growth, proliferation, and angiogenesis, in both imatinib-sensitive and imatinib-resistant models.

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

• Sensitive Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Molecule Alteration: Complex-indel; p.K558_G565delinsR (c.1673_1693del21)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Clinical GIST specimens; N.A.
• In Vivo Model: NMRI mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: Cabozantinib inhibited the KIT signaling pathway in UZLX-GIST4 and -GIST2. In addition, compared with both control and imatinib, cabozantinib significantly reduced microvessel density in all models. Cabozantinib showed antitumor activity in GIST PDX models through inhibition of tumor growth, proliferation, and angiogenesis, in both imatinib-sensitive and imatinib-resistant models.

Colorectal cancer [ICD-11: 2B91]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: VEGF-2 receptor (KDR) [11]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.R1032Q (c.3095G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: VEGF signaling pathway; Activation; 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.

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) [3]

• 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: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [3]

• 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) [3]

• 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.

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Hepatocyte growth factor receptor (MET) [4]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.D1228N (c.3682G>A)
• 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: Hepatocyte growth factor receptor (MET) [12]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.Y1003N (c.3007T>A)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Hepatocyte growth factor receptor (MET) [12]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.Y1003C (c.3008A>G)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Hepatocyte growth factor receptor (MET) [12]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.Y1003F (c.3008A>T)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Hepatocyte growth factor receptor (MET) [12]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.D1010N (c.3028G>A)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Hepatocyte growth factor receptor (MET) [12]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.D1010H (c.3028G>C)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Hepatocyte growth factor receptor (MET) [12]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.D1010Y (c.3028G>T)
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Proto-oncogene c-Ros (ROS1) [13]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.G2032R (c.6094G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HEK293 FT cells; Kidney; Homo sapiens (Human); CVCL_6911
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Key Molecule: Proto-oncogene c-Ros (ROS1) [14]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.G2032R (c.6094G>A)
• Experimental Note: Identified from the Human Clinical Data

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Hepatocyte growth factor receptor (MET) [7]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.D1228V (c.3683A>T)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.71 Å; PDB: 5HNI
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.67 Å; PDB: 6SDC

RMSD: 1.85; TM score: 0.88477; Amino acid change: D1228V

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: There is a patient with metastatic NSCLC with MET-mediated resistance to EGFR TKI who responded to treatment with a type I MET inhibitor, savolitinib, given in combination with a third-generation EGFR inhibitor, osimertinib. The patient then developed acquired resistance mediated by a novel MET kinase domain mutation.

Kidney cancer [ICD-11: 2C90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Pro-angiogenic factors [2]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: VeroE6/TMPRSS2 cells; Kidney; Chlorocebus sabaeus (Green monkey) (Cercopithecus sabaeus); CVCL_YQ49
• In Vitro Model: HUVEC cells; Endothelium; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Secreted protein measurements assay
• Experiment for Drug Resistance: Flow cytometry
• Mechanism Description: We show that circulating immune cells from patients with ccRCC induce cabozantinib resistance via increased secretion of a set of pro-angiogenic factors.

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) [15]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.64 Å; PDB: 7DUA
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.12 Å; PDB: 4CKI

RMSD: 0.93; TM score: 0.95555; Amino acid change: M918T

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: MTC-TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.M918T (c.2753T>C) in gene RET cause the sensitivity of Cabozantinib by aberration of the drug's therapeutic target

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [16]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.64 Å; PDB: 7DUA
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.12 Å; PDB: 4CKI

RMSD: 0.93; TM score: 0.95555; Amino acid change: M918T

• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [15]

• 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: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: MTC-TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.C634W (c.1902C>G) in gene RET cause the sensitivity of Cabozantinib by aberration of the drug's therapeutic target

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [17]

• 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: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vivo Model: Female nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Kinase inhibition assay
• Mechanism Description: The missense mutation p.C634W (c.1902C>G) in gene RET cause the sensitivity of Cabozantinib by unusual activation of pro-survival pathway

Multiple endocrine neoplasia [ICD-11: 2F7A]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]

• Resistant Disease: Multiple endocrine neoplasia [ICD-11: 2F7A.0]
• Molecule Alteration: Missense mutation; p.M918T
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.64 Å; PDB: 7DUA
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.12 Å; PDB: 4CKI

RMSD: 0.93; TM score: 0.95555; Amino acid change: M918T

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: BaF3 cells; Bone; Mus musculus (Mouse); CVCL_0161
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: LC50 assay
• Mechanism Description: M918T is a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B. M918T mutation is located at distant sites away from the TKI binding pocket. IC50s of cabozantinib, lenvatinib, vandetanib and nintedanib in BaF3/KR (M918T) cells were 6.5-fold, 7.5-fold, 4.3-fold and 1.7-fold, respectively, higher than in BaF3/KR cells.

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]

• Resistant Disease: Multiple endocrine neoplasia [ICD-11: 2F7A.0]
• Molecule Alteration: Missense mutation; p.M918T
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.64 Å; PDB: 7DUA
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.12 Å; PDB: 4CKI

RMSD: 0.93; TM score: 0.95555; Amino acid change: M918T

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: BaF3 cells; Bone; Mus musculus (Mouse); CVCL_0161
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: LC50 assay
• Mechanism Description: M918T is a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B. M918T mutation is located at distant sites away from the TKI binding pocket. IC50s of cabozantinib, lenvatinib, vandetanib and nintedanib in BaF3/KR (M918T) cells were 6.5-fold, 7.5-fold, 4.3-fold and 1.7-fold, respectively, higher than in BaF3/KR cells.

References

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