NTRK3

Overview

NTRK3 (Neurotrophic Receptor Tyrosine Kinase 3, also TRKC) is a member of the neurotrophin receptor family. The canonical ETV6–NTRK3 fusion is the defining genomic event of infantile fibrosarcoma (IFS) and is also found in secretory breast carcinoma, mammary analogue secretory carcinoma, and other tumor types. NTRK3 fusions are pan-tumor-agnostic targets for TRK inhibitors (larotrectinib, entrectinib) approved by the FDA.

Alterations observed in the corpus

  • ETV6–NTRK3 fusion is the canonical driver of infantile fibrosarcoma (IFS); in the 194-specimen UCLA sarcoma PDTO screen, SARC0127 was initially presumed to be IFS but was FISH-negative for ETV6 and exhibited larotrectinib resistance in the PDTO, leading to reclassification as SCSRMS (spindle cell/sclerosing rhabdomyosarcoma). This case illustrates that NTRK3 FISH-negativity combined with PDTO larotrectinib non-response can drive diagnostic reclassification. PMID:39305899
  • Oncogenic NTRK3 fusions listed among OncoKB level 1 or 2 biomarkers in the MSK 2,336-patient PDAC cohort (alongside NTRK1/RET fusions), constituting part of the ~10% of patients with high-level actionable alterations. PMID:39753968
  • Part of NTRK family (NTRK1/2/3) with 20 total mutations in 188 LUAD tumours, 7 in kinase domains; recurrent somatic mutations establish NTRK3 as a LUAD candidate driver. PMID:18948947
  • Discussed as analogous context: NTRK3 fusions in other cancers provide precedent for the NTRK2 kinase-domain-retaining fusions newly described in pilocytic astrocytoma PMID:23817572
  • NTRK3 fusions (ETV6/NTRK3 and RBPMS/NTRK3) in 1.2% (6/484) PTC tumors; fusions were BRS-neutral in the BVL/RL transcriptome classification PMID:25417114
  • NTRK1/2/3 fusions reported in ~0.2% of CCA overall, up to 3.6% of intrahepatic CCA; targetable with entrectinib and larotrectinib PMID:25526346
  • NTRK3 fusions in thyroid cancer could not be assessed because the IMPACT 341-gene panel does not cover NTRK3 intronic regions; explicitly flagged as a detection gap in the study of PDTC and ATC PMID:26878173
  • Mentioned as a rare fusion target in young lung cancer (YLC) with scarce age-stratified frequency data PMID:27346245
  • ETV6-NTRK3 fusion identified in 2 tumors initially diagnosed as acinic cell carcinoma, reclassifying them as mammary analogue secretory carcinoma (MASC); both patients responded to a TRK inhibitor on a basket trial PMID:27442865
  • EML4–NTRK3 fusion in congenital fibrosarcoma (IFS) supported diagnostic reclassification from undifferentiated sarcoma to infantile fibrosarcoma; ALK-inhibitor target identified in a pediatric precision-oncology cohort PMID:28007021
  • Fusions present in 8% of MSI-H vs 1% of MSS mCRC; specific fusion identified: ETV6-NTRK3; TRK-inhibitor candidates in MSI-H mCRC PMID:29316426
  • Among the top recurrent 3’-kinase tyrosine kinases enriched in THCA (thyroid carcinoma) fusions in pan-cancer RNA-seq analysis of 9,624 TCGA samples; 94% of THCA kinase fusions involve 3’-enriched kinases including NTRK1, NTRK3, and BRAF. PMID:29617662

Cancer types (linked)

Co-occurrence and mutual exclusivity

  • In sarcoma, ETV6–NTRK3 fusion is nearly exclusive to IFS; its absence (FISH-negative) in SARC0127 redirected diagnosis to SCSRMS, which has overlapping histology but distinct biology and therapeutic implications. PMID:39305899

Therapeutic relevance

  • Larotrectinib is FDA-approved for NTRK fusion-positive solid tumors; the PDTO platform demonstrated that functional larotrectinib resistance in SARC0127 — alongside FISH-negative ETV6 — guided reclassification and avoided a likely ineffective targeted therapy. PMID:39305899
  • NTRK3 fusions in PDAC are rare (included in the ~10% with level 1/2 actionable alterations); treatment decisions should integrate NTRK inhibitor eligibility for confirmed fusion carriers. PMID:39753968

Open questions

  • Mechanism of larotrectinib resistance in the NTRK3-negative SARC0127 (reclassified as SCSRMS) versus canonical kinase-domain resistance mutations in NTRK3-positive cancers is not explored in this corpus. PMID:39305899

Sources

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