Drug Information

Drug (ID: DG01263) and It's Reported Resistant Information

• Name: Larotrectinib
• Synonyms: Larotrectinib; LOXO-101; 1223403-58-4; ARRY-470; (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; LOXO 101; UNII-PF9462I9HX; LOXO101; PF9462I9HX; (3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide; BAY2757556; BAY-2757556; Vitrakvi; ARRY 470; 1-Pyrrolidinecarboxamide, N-(5-((2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl)pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxy-, (3S)-; 1-Pyrrolidinecarboxamide, N-[5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxy-, (3S)-; ARRY-470; larotrectinib; Larotrectinib (USAN/INN); Larotrectinib [USAN:INN]; ARRY470; AMY264; GTPL8909; SCHEMBL2241012; CHEMBL3889654; BDBM136597; BCP16262; EX-A1981; MFCD28902192; NSC785570; NSC801004; s5860; Larotrectinib (LOXO-101 free base); example 14 [US8865698 B2]; ZINC118399834; CS-5722; DB14723; NSC-785570; NSC-801004; AC-33660; AS-35231; HY-12866; J3.628.138C; D11137; US8865698, 14; Q27081513; ARRY-470;ARRY 470 : LOXO-101; LOXO101; Larotrectinib; ARRY470;ARRY-470;ARRY 470;LOXO 101;LOXO101;Larotrectinib; (3S)-N-(5-((2R)-2-(2,5-Difluorophenyl)pyrrolidin-1-yl)pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxypyrrolidine- 1-carboxamide; (S)-N-(5 -((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin -1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3 yl)-3-hydroxypyrrolidine-1-carboxamide
• Indication:
  In total 3 Indication(s)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [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)
  Colorectal cancer [ICD-11: 2B91]; [3]
  Rhabdomyosarcoma [ICD-11: 2B55]; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [4]
• Target: BDNF/NT-3 growth factors receptor (TrkB); NTRK2_HUMAN; [1]
• Target: NT-3 growth factor receptor (TrkC); NTRK3_HUMAN; [1]
• Target: Tropomyosin-related kinase A (TrkA); NTRK1_HUMAN; [1]
• Formula: C21H22F2N6O2
• IsoSMILES: C1C[C@@H](N(C1)C2=NC3=C(C=NN3C=C2)NC(=O)N4CC[C@@H](C4)O)C5=C(C=CC(=C5)F)F
• InChI: 1S/C21H22F2N6O2/c22-13-3-4-16(23)15(10-13)18-2-1-7-28(18)19-6-9-29-20(26-19)17(11-24-29)25-21(31)27-8-5-14(30)12-27/h3-4,6,9-11,14,18,30H,1-2,5,7-8,12H2,(H,25,31)/t14-,18+/m0/s1
• InChIKey: NYNZQNWKBKUAII-KBXCAEBGSA-N
• PubChem CID: 46188928
• TTD Drug ID: D07TOK

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

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; 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.

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: Tropomyosin-related kinase A (TrkA) [4]

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

Key Molecule: NT-3 growth factor receptor (TrkC) [4]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.G623R (c.1867G>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: NT-3 growth factor receptor (TrkC) [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Other; .
• Experimental Note: Identified from the Human Clinical Data

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: NT-3 growth factor receptor (TrkC) [6]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Other; .
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay

Rhabdomyosarcoma [ICD-11: 2B55]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tropomyosin-related kinase A (TrkA) [1]

• Resistant Disease: Metastatic undifferentiated sarcoma [ICD-11: 2B55.Y]
• Molecule Alteration: Missense mutation; p.G595R
• 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: NTHY-ORI-3-1 cells; Thyroid gland; Homo sapiens (Human); CVCL_2659
• Mechanism Description: After 6 months on study, restaging scans identified an isolated area of progression in the right hepatic lobe, which was resected (S3), followed by resumption of larotrectinib. NGS from S3 identified an NTRK1 G595R solvent-front mutation. Three months later, diffuse disease was noted on restaging scans.

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: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: KM-12 cells; Colon; Homo sapiens (Human); CVCL_1331
• In Vivo Model: Balb-c nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Sanger sequencing assay; Western blot analysis
• Experiment for Drug Resistance: CellTiter Glo assay; IC50 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: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: KM-12 cells; Colon; Homo sapiens (Human); CVCL_1331
• In Vivo Model: Balb-c nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Sanger sequencing assay; Western blot analysis
• Experiment for Drug Resistance: CellTiter Glo assay; IC50 assay

References

• Ref 1: Response and mechanisms of resistance to larotrectinib and selitrectinib in metastatic undifferentiated sarcoma harboring oncogenic fusion of NTRK1 .JCO Precis Oncol. 2020;4:79-90. doi: 10.1200/po.19.00287. Epub 2020 Feb 14. 10.1200/po.19.00287
• 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: Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged CancersMol Cancer Ther. 2017 Oct;16(10):2130-2143. doi: 10.1158/1535-7163.MCT-16-0909. Epub 2017 Jul 27.
• Ref 4: A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid TumorsCancer Discov. 2017 Sep;7(9):963-972. doi: 10.1158/2159-8290.CD-17-0507. Epub 2017 Jun 3.
• Ref 5: Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation studyAnn Oncol. 2019 Feb 1;30(2):325-331. doi: 10.1093/annonc/mdy539.
• Ref 6: Clinical response to larotrectinib in adult Philadelphia chromosome-like ALL with cryptic ETV6-NTRK3 rearrangementBlood Adv. 2020 Jan 14;4(1):106-111. doi: 10.1182/bloodadvances.2019000769.