Drug Information

Drug (ID: DG00618) and It's Reported Resistant Information

• Name: Lenvatinib
• Synonyms: Lenvatinib; 417716-92-8; E7080; Lenvima; 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide; E7080 (Lenvatinib); Lenvatinib (E7080); E 7080; E-7080; Lenvatinib free base; ER-203492-00; UNII-EE083865G2; 4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide; 4-{3-Chloro-4-[(Cyclopropylcarbamoyl)amino]phenoxy}-7-Methoxyquinoline-6-Carboxamide; 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide; CHEMBL1289601; CHEBI:85994; 417716-92-8 (free base); EE083865G2; 4-(3-chloro-4-(N'-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide; Lenvatinib [USAN:INN]; Kisplyx; 4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; LEV; LenvatinibE7080); Lenvatinib; E7080; Lenvatinib base- Bio-X; Lenvatinib (USAN/INN); MLS006011239; SCHEMBL864638; GTPL7426; AMY9240; DTXSID50194605; EX-A249; QCR-115; SYN1038; BCPP000247; HMS3244A07; HMS3244A08; HMS3244B07; HMS3654A14; AOB87766; BCP01799; ZINC3816292; BDBM50331094; MFCD16038644; NSC755980; NSC800781; s1164; AKOS025401742; BCP9000633; CCG-264842; CS-0109; DB09078; NSC-755980; NSC-800781; SB16580; 4-(3-chloro-4-((cyclopropylaminocarbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; NCGC00263198-01; NCGC00263198-04; NCGC00263198-07; AC-25047; AS-16203; BL164616; HY-10981; SMR004702999; DB-070219; FT-0700727; SW219259-1; D09919; 716C928; A825653; J-513372; Q6523413; BRD-K39974922-001-02-7; 4-[3-chloranyl-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide; 4-[3-Chloro-4-[[(cyclopropylamino)carbonyl]amino]phenoxy]-7-methoxy-6-quinolinecarboxamide; 4-[3-chloro-4-[[(cyclopropylamino)-oxomethyl]amino]phenoxy]-7-methoxy-6-quinolinecarboxamide; 6-Quinolinecarboxamide, 4-(3-chloro-4- (((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-
• Indication:
  In total 8 Indication(s)
  Renal cell carcinoma [ICD-11: 2C90]; Phase 3; [1]
  Hepatocellular carcinoma [ICD-11: 2C12]; Phase 1; [1]
  Non-small-cell lung cancer [ICD-11: 2C25]; Phase 1; [1]
  Thyroid cancer [ICD-11: 2D10]; Phase 1; [1]
  Hepatocellular carcinoma [ICD-11: 2C12]; Phase 2; [1]
  Melanoma [ICD-11: 2C30]; Phase 2; [1]
  Ovarian cancer [ICD-11: 2C73]; Phase 2; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Phase 2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Multiple endocrine neoplasia [ICD-11: 2F7A]; [2]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Liver cancer [ICD-11: 2C12]; [1]
• Target: .; NOUNIPROTAC; [1]
• Formula: C21H19ClN4O4
• IsoSMILES: COC1=CC2=NC=CC(=C2C=C1C(=O)N)OC3=CC(=C(C=C3)NC(=O)NC4CC4)Cl
• InChI: 1S/C21H19ClN4O4/c1-29-19-10-17-13(9-14(19)20(23)27)18(6-7-24-17)30-12-4-5-16(15(22)8-12)26-21(28)25-11-2-3-11/h4-11H,2-3H2,1H3,(H2,23,27)(H2,25,26,28)
• InChIKey: WOSKHXYHFSIKNG-UHFFFAOYSA-N
• PubChem CID: 9823820
• TTD Drug ID: D03KSK
• VARIDT ID: DR00265
• DrugBank ID: DB09078

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 Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [3]

• Molecule Alteration: Missense mutation; p.K660E (c.1978A>G)
• 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: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Soft-agar colony formation assay
• Mechanism Description: The missense mutation p.K660E (c.1978A>G) in gene FGFR2 cause the sensitivity of Lenvatinib by aberration of the drug's therapeutic target

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [3]

• Molecule Alteration: Missense mutation; p.K660N (c.1980G>C)
• 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: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Soft-agar colony formation assay
• Mechanism Description: The missense mutation p.K660N (c.1980G>C) in gene FGFR2 cause the sensitivity of Lenvatinib by aberration of the drug's therapeutic target

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [3]

• Molecule Alteration: Missense mutation; p.W290C (c.870G>T)
• 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: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Soft-agar colony formation assay
• Mechanism Description: The missense mutation p.W290C (c.870G>T) in gene FGFR2 cause the sensitivity of Lenvatinib by aberration of the drug's therapeutic target

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) [4]

• Molecule Alteration: Missense mutation; p.R1032Q (c.3095G>A)
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• 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 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.

Liver cancer [ICD-11: 2C12]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dual specificity phosphatase 9 (DUSP9) [1]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: MAPK/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: FOXO3 signaling pathway; Inhibition; hsa04068
• In Vivo Model: Xenograft-nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Quantitative RT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay; Transwell invasion assay
• Mechanism Description: With RNAi knockdown and CRISPR/Cas9 knockout models, we further clarified the mechanisms by which NF1 loss reactivates the PI3K/AKT and MAPK/ERK signaling pathways, while DUSP9 loss activates the MAPK/ERK signaling pathways, thereby inactivating FOXO3, followed by degradation of FOXO3, finally induced lenvatinib resistance.

Key Molecule: Neurofibromin (NF1) [1]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: MAPK/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: FOXO3 signaling pathway; Inhibition; hsa04068
• In Vivo Model: Xenograft-nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Quantitative RT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay; Transwell invasion assay
• Mechanism Description: With RNAi knockdown and CRISPR/Cas9 knockout models, we further clarified the mechanisms by which NF1 loss reactivates the PI3K/AKT and MAPK/ERK signaling pathways, while DUSP9 loss activates the MAPK/ERK signaling pathways, thereby inactivating FOXO3, followed by degradation of FOXO3, finally induced lenvatinib resistance.

Thyroid cancer [ICD-11: 2D10]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [5]

• 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: FTC-133 cells; Thyroid; Homo sapiens (Human); CVCL_1219
• In Vitro Model: 8305C cells; Thyroid; Homo sapiens (Human); CVCL_1053
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: KHM-5M cells; Pleural effusion; Homo sapiens (Human); CVCL_2975
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: TCO-1 cells; Lnguinal lymph node; Homo sapiens (Human); CVCL_3179
• In Vitro Model: RO82-W-1 cells; Thyroid; Homo sapiens (Human); CVCL_0582/CVCL_1663
• In Vitro Model: Nthy-ori 3-1 cells; N.A.; Homo sapiens (Human); CVCL_2659
• In Vitro Model: K1 cells; Thyroid; Homo sapiens (Human); CVCL_2537
• In Vitro Model: HTC-C3 cells; Pleural effusion; Homo sapiens (Human); CVCL_2273
• In Vitro Model: FTC-238 cells; Lung; Homo sapiens (Human); CVCL_2447
• In Vitro Model: FTC-236 cells; Cervical lymph node; Homo sapiens (Human); CVCL_2446
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; ICH assay
• Experiment for Drug Resistance: MSA assay; WST-8 assay

Multiple endocrine neoplasia [ICD-11: 2F7A]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [2]

• Molecule Alteration: Missense mutation; p.M918T
• Resistant Disease: Multiple endocrine neoplasia [ICD-11: 2F7A.0]
• 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) [2]

• Molecule Alteration: Missense mutation; p.M918T
• Resistant Disease: Multiple endocrine neoplasia [ICD-11: 2F7A.0]
• 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

• Ref 1: Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance .Cell Death Discov. 2021 Nov 18;7(1):359. doi: 10.1038/s41420-021-00747-y. 10.1038/s41420-021-00747-y
• Ref 2: Drug resistance profiles of mutations in the RET kinase domain .Br J Pharmacol. 2018 Sep;175(17):3504-3515. doi: 10.1111/bph.14395. Epub 2018 Jul 19. 10.1111/bph.14395
• Ref 3: Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinomaCancer Res. 2013 Aug 15;73(16):5195-205. doi: 10.1158/0008-5472.CAN-12-3950. Epub 2013 Jun 20.
• Ref 4: Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic TherapiesClin Cancer Res. 2018 Aug 1;24(15):3550-3559. doi: 10.1158/1078-0432.CCR-18-0103. Epub 2018 Mar 27.
• Ref 5: Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer modelsJ Thyroid Res. 2014;2014:638747. doi: 10.1155/2014/638747. Epub 2014 Sep 10.