Molecule Information

General Information of the Molecule (ID: Mol01831)

• Name: Tropomyosin-related kinase A (TrkA) ,Homo sapiens
• Synonyms: Neurotrophic tyrosine kinase receptor type 1; TRK1-transforming tyrosine kinase protein; Tropomyosin-related kinase A; Tyrosine kinase receptor; Tyrosine kinase receptor A; Trk-A; gp140trk; p140-TrkA; NTRK1; MTC; TRK; TRKA
• Molecule Type: Protein
• Gene Name: NTRK1
• Gene ID: 4914
• Location: chr1:156,815,640156,881,850[+]
• Sequence:
  MLRGGRRGQLGWHSWAAGPGSLLAWLILASAGAAPCPDACCPHGSSGLRCTRDGALDSLH
  HLPGAENLTELYIENQQHLQHLELRDLRGLGELRNLTIVKSGLRFVAPDAFHFTPRLSRL
  NLSFNALESLSWKTVQGLSLQELVLSGNPLHCSCALRWLQRWEEEGLGGVPEQKLQCHGQ
  GPLAHMPNASCGVPTLKVQVPNASVDVGDDVLLRCQVEGRGLEQAGWILTELEQSATVMK
  SGGLPSLGLTLANVTSDLNRKNVTCWAENDVGRAEVSVQVNVSFPASVQLHTAVEMHHWC
  IPFSVDGQPAPSLRWLFNGSVLNETSFIFTEFLEPAANETVRHGCLRLNQPTHVNNGNYT
  LLAANPFGQASASIMAAFMDNPFEFNPEDPIPVSFSPVDTNSTSGDPVEKKDETPFGVSV
  AVGLAVFACLFLSTLLLVLNKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTE
  GKGSGLQGHIIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKML
  VAVKALKEASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVFEYMRHGDLNRF
  LRSHGPDAKLLAGGEDVAPGPLGLGQLLAVASQVAAGMVYLAGLHFVHRDLATRNCLVGQ
  GLVVKIGDFGMSRDIYSTDYYRVGGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEI
  FTYGKQPWYQLSNTEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHAR
  LQALAQAPPVYLDVLG
• Function: Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand. Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors.; [Isoform TrkA-III]: Resistant to NGF, it constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.
• Uniprot ID: NTRK1_HUMAN
• Ensembl ID: ENSG00000198400
• HGNC ID: HGNC:8031

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Entrectinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Colorectal cancer [1]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Entrectinib
• 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

Disease Class: Colorectal cancer [1]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Entrectinib
• Molecule Alteration: Missense mutation; p.G595R (c.1783G>A)
• 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

Larotrectinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Colorectal cancer [2]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Larotrectinib
• Molecule Alteration: Missense mutation; p.G595R (c.1783G>A)
• 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 blotting analysis
• Experiment for Drug Resistance: CellTiter Glo assay; IC50 assay

Disease Class: Colorectal cancer [2]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Larotrectinib
• 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 blotting analysis
• Experiment for Drug Resistance: CellTiter Glo assay; IC50 assay

Disease Class: Solid tumour/cancer [3]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: Larotrectinib
• Molecule Alteration: Missense mutation; p.G595R (c.1783G>A)
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Metastatic undifferentiated sarcoma [4]

• Resistant Disease: Metastatic undifferentiated sarcoma [ICD-11: 2B55.Y]
• Resistant Drug: Larotrectinib
• Molecule Alteration: Missense mutation; p.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.

Preclinical Drug(s) 1 drug(s) in total

Pan-TRK inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Colorectal cancer [1]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Pan-TRK inhibitors
• 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

Disease Class: Colorectal cancer [1]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Pan-TRK inhibitors
• Molecule Alteration: Missense mutation; p.G595R (c.1783G>A)
• 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

References

• Ref 1: 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 2: 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 3: 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 4: 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