Molecule Information

General Information of the Molecule (ID: Mol01828)

• Name: NT-3 growth factor receptor (TrkC) ,Homo sapiens
• Synonyms: GP145-TrkC; Trk-C; Neurotrophic tyrosine kinase receptor type 3; TrkC tyrosine kinase; NTRK3; TRKC
• Molecule Type: Protein
• Gene Name: NTRK3
• Gene ID: 4916
• Location: chr15:87,859,75188,256,791[-]
• Sequence:
  MDVSLCPAKCSFWRIFLLGSVWLDYVGSVLACPANCVCSKTEINCRRPDDGNLFPLLEGQ
  DSGNSNGNASINITDISRNITSIHIENWRSLHTLNAVDMELYTGLQKLTIKNSGLRSIQP
  RAFAKNPHLRYINLSSNRLTTLSWQLFQTLSLRELQLEQNFFNCSCDIRWMQLWQEQGEA
  KLNSQNLYCINADGSQLPLFRMNISQCDLPEISVSHVNLTVREGDNAVITCNGSGSPLPD
  VDWIVTGLQSINTHQTNLNWTNVHAINLTLVNVTSEDNGFTLTCIAENVVGMSNASVALT
  VYYPPRVVSLEEPELRLEHCIEFVVRGNPPPTLHWLHNGQPLRESKIIHVEYYQEGEISE
  GCLLFNKPTHYNNGNYTLIAKNPLGTANQTINGHFLKEPFPESTDNFILFDEVSPTPPIT
  VTHKPEEDTFGVSIAVGLAAFACVLLVVLFVMINKYGRRSKFGMKGPVAVISGEEDSASP
  LHHINHGITTPSSLDAGPDTVVIGMTRIPVIENPQYFRQGHNCHKPDTYVQHIKRRDIVL
  KRELGEGAFGKVFLAECYNLSPTKDKMLVAVKALKDPTLAARKDFQREAELLTNLQHEHI
  VKFYGVCGDGDPLIMVFEYMKHGDLNKFLRAHGPDAMILVDGQPRQAKGELGLSQMLHIA
  SQIASGMVYLASQHFVHRDLATRNCLVGANLLVKIGDFGMSRDVYSTDYYRLFNPSGNDF
  CIWCEVGGHTMLPIRWMPPESIMYRKFTTESDVWSFGVILWEIFTYGKQPWFQLSNTEVI
  ECITQGRVLERPRVCPKEVYDVMLGCWQREPQQRLNIKEIYKILHALGKATPIYLDILG
• Function: Receptor tyrosine kinase involved in nervous system and probably heart development. Upon binding of its ligand NTF3/neurotrophin-3, NTRK3 autophosphorylates and activates different signaling pathways, including the phosphatidylinositol 3-kinase/AKT and the MAPK pathways, that control cell survival and differentiation.
• Uniprot ID: NTRK3_HUMAN
• Ensembl ID: ENSG00000140538
• HGNC ID: HGNC:8033

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

  EADR: Epigenetic Alteration of DNA, RNA or Protein

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: Mammary analogue secretory carcinoma [1]

• Resistant Disease: Mammary analogue secretory carcinoma [ICD-11: 2F30.1]
• Resistant Drug: Entrectinib
• 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.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Breast adenocarcinoma [1]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Entrectinib
• 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.

Larotrectinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [2]

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

Disease Class: Solid tumour/cancer [3]

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

Disease Class: Acute lymphocytic leukemia [4]

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

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.04E-68; Fold-change: -7.26E-01; Z-score: -1.65E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 7.72E-06; Fold-change: -4.19E-01; Z-score: -6.70E-01

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: 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 3: 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 4: 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.