Drug Information

Drug (ID: DG01248) and It's Reported Resistant Information

• Name: Entrectinib
• Synonyms: Entrectinib; 1108743-60-7; NMS-E628; RXDX-101; Rozlytrek; UNII-L5ORF0AN1I; Entrectinib (RXDX-101); Entrectinib(rxdx-101); L5ORF0AN1I; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide; N-{5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl}-4-(4-methylpiperazin-1-yl)-2-[(oxan-4-yl)amino]benzamide; Benzamide, N-(5-((3,5-difluorophenyl)methyl)-1H-indazol-3-yl)-4-(4-methyl-1-piperazinyl)-2-((tetrahydro-2H-pyran-4-yl)amino)-; Benzamide, N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methyl-1-piperazinyl)-2-[(tetrahydro-2H-pyran-4-yl)amino]-; Entrectinib [USAN:INN]; Rozlytrek (TN); YMX; Entrectinib, 95%; Kinome_2659; Entrectinib; NMS-E628; Entrectinib (JAN/USAN/INN); GTPL8290; SCHEMBL3512601; CHEMBL1983268; NMS-E-628; NMS-E628;RXDX-101; HMS3886H21; BCP16174; EX-A2261; MFCD28129099; NSC774769; NSC800095; s7998; ZINC43204146; CCG-270048; DB11986; NSC-774769; NSC-800095; SB17194; NCGC00484067-01; NCGC00484067-02; NCGC00484067-03; AC-31286; AS-75092; DA-47850; HY-12678; N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazin-1yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide; B5859; FT-0736318; D10926; A856078; Q25323953; S900006830; RXDX101; RXDX 101; RXDX-101; NMS E628; NMS-E628;NMS E628; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methyl-1-piperazinyl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide; N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; N-{5-[(3,5-difluorophenyl)methyl]-3H-indazol-3-ylidene}-4-(4-methylpiperazin-1-yl)-2-[(oxan-4-yl)amino]benzamide
• Indication:
  In total 7 Indication(s)
  Colorectal cancer [ICD-11: 2B91]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Patented; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Phase 1; [1]
  Colorectal cancer [ICD-11: 2B91]; Investigative; [1]
  Mammary analogue secretory carcinoma [ICD-11: 2C60-2C6Y]; Investigative; [1]
  Neuroblastoma [ICD-11: 2A00]; Investigative; [1]
  Non-small cell lung cancer [ICD-11: 2C25]; Investigative; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Brain cancer [ICD-11: 2A00]; [2]
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Breast cancer [ICD-11: 2C60]; [1]
  Breast lactating adenoma [ICD-11: 2F30]; [1]
  Colorectal cancer [ICD-11: 2B91]; [3]
• Formula: C31H34F2N6O2
• IsoSMILES: CN1CCN(CC1)C2=CC(=C(C=C2)C(=O)NC3=NNC4=C3C=C(C=C4)CC5=CC(=CC(=C5)F)F)NC6CCOCC6
• InChI: 1S/C31H34F2N6O2/c1-38-8-10-39(11-9-38)25-3-4-26(29(19-25)34-24-6-12-41-13-7-24)31(40)35-30-27-17-20(2-5-28(27)36-37-30)14-21-15-22(32)18-23(33)16-21/h2-5,15-19,24,34H,6-14H2,1H3,(H2,35,36,37,40)
• InChIKey: HAYYBYPASCDWEQ-UHFFFAOYSA-N
• PubChem CID: 25141092
• TTD Drug ID: D0H6JK
• INTEDE ID: DR0582
• DrugBank ID: DB11986

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Brain cancer [ICD-11: 2A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tropomyosin-related kinase A (TrkA) [2]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Missense mutation; F589L; G595R; G667C; F589L-G595R
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NIH-3T3-tv-a cells; Embryo; Homo sapiens (Human); N.A.
• In Vivo Model: RCAS/tv-a system 19. Nestin (N)/tv-a mouse model; Cdkn2a-wild type mouse model; Null mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay; RT-PCR
• Experiment for Drug Resistance: Quantification of Larotrectinib tissue levels assay; Spheroid assay; Magnetic resonance imaging assay; H&E staining assay; Immunohistochemistry staining assay
• Mechanism Description: Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ALK tyrosine kinase receptor (ALK) [4]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.F1245V (c.3733T>G)
• Experimental Note: Identified from the Human Clinical Data

Colorectal cancer [ICD-11: 2B91]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tropomyosin-related kinase A (TrkA) [3]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.G595R (c.1783G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.10 Å; PDB: 5H3Q
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.09 Å; PDB: 8J5X

RMSD: 1.34; TM score: 0.93325; Amino acid change: G595R

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: KM-12 cells; Colon; Homo sapiens (Human); CVCL_1331
• In Vivo Model: NOD-SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: ddPCR; Kinase domain alignment assay

Key Molecule: Tropomyosin-related kinase A (TrkA) [3]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.G667C (c.1999G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: KM-12 cells; Colon; Homo sapiens (Human); CVCL_1331
• In Vivo Model: NOD-SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: ddPCR; Kinase domain alignment assay

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: NT-3 growth factor receptor (TrkC) [1]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Molecule Alteration: Missense mutation; p.G623R (c.1867G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Fluorescence in situ hybridization assay; Mutational profiling of actionable cancer targets assay
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Recurrent gene rearrangements such as ETV6-NTRK3 are a critical mechanism of oncogenic activation for the neurotrophic tyrosine receptor kinase genes, NTRK1, NTRK2, and NTRK3, in human malignancies. Fusion of the intact tyrosine kinase domain of NTRK1, NTRK2, or NTRK3 with a variety of upstream partners results in dysregulated activation of several biochemical signaling pathways that promote oncogenic initiation and growth.

Breast lactating adenoma [ICD-11: 2F30]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: NT-3 growth factor receptor (TrkC) [1]

• Resistant Disease: Mammary analogue secretory carcinoma [ICD-11: 2F30.1]
• Molecule Alteration: Missense mutation; p.G623R
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Mechanism Description: A dramatic and durable response was achieved with entrectinib in this patient, followed by acquired resistance that correlated with the appearance of a novel NTRK3 G623R mutation. Investigation into the structural impact of the G623R point mutation revealed a potential mechanism of relative resistance to entrectinib and other Trk inhibitors. The NTRK3 G623R mutation creates steric hindrance that functionally reduces the binding of entrectinib with mutant TrkC.

References

• Ref 1: What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC) .Ann Oncol. 2016 May;27(5):920-6. doi: 10.1093/annonc/mdw042. Epub 2016 Feb 15. 10.1093/annonc/mdw042
• Ref 2: ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models. Cell Rep. 2024 Oct 22;43(10):114829.
• Ref 3: Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal CancerCancer Discov. 2016 Jan;6(1):36-44. doi: 10.1158/2159-8290.CD-15-0940. Epub 2015 Nov 6.
• Ref 4: Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1)Cancer Discov. 2017 Apr;7(4):400-409. doi: 10.1158/2159-8290.CD-16-1237. Epub 2017 Feb 9.