• What is NTRK1?
  • NTRK1 in Lung Cancer
  • NTRK1 (TRKA) Fusions
  • Clinical Trials

NTRK1 (TRKA)

NTRK1 (neurotrophic tyrosine kinase, receptor, type 1) is a receptor tyrosine kinase that is part of the TRK (tropomyosin-related kinases) superfamily of receptor tyrosine kinases (Nakagawara 2001; Sossin 2006). The NTRK1 gene is located on chromosome 1q21-22 and encodes high affinity nerve growth factor receptor (TRKA). NTRK1 acts in control of cell growth and differentiation via the MAPK, PI3K and PLC-γ pathways when activated by the NGF ligand (Alberti et al. 2003).

NTRK1 fusions were initially reported in one case of colorectal cancer (Martin-Zanca et al. 1986). NTRK1 rearrangements have been reported in 12% of papillary thyroid cancer (Greco et al. 2010), 3.3% of lung cancer (Vaishnavi et al. 2013), and approximately 1% of glioblastoma multiforme cases (Greco et al. 2010; Kim et al. 2014). Recently, one case of a RABGAP1L-NTRK1 fusion has been reported in cholangiocarcinoma (Ross et al. 2014). In colorectal and thyroid cancer, the fusion partners include TPM3, TFG and TPR (Martin-Zanca et al. 1986). In lung cancer, fusion partners identified include MPRIP and CD74 (Vaishnavi et al. 2013).

NTRK1 gene fusions include the entire kinase domain of TRKA (the protein product from the NTRK1 gene). NTRK1 gene fusions tested trigger constitutive TRKA kinase activity (Vaishnavi et al. 2013).

ntrk1-pathway.png

Figure 1.
Schematic representation of NTRK1 (TRKA) fusions. "X" represents the various fusion partners that have been described. Dimerization of the NTRK1 fusion mediated by the fusion partner ("X"), results in constitutive activation of the NTRK1 tyrosine kinase. NTRK1 signaling results in pro-growth and anti-apoptosis effects.

Related Pathways

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Contributors: Christine M. Lovly, M.D., Ph.D., Robert C. Doebele, M.D., Ph.D.

Suggested Citation: Lovly, C., R. Doebele. 2015. NTRK1 (TRKA). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/ntrk1/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

NTRK1 (TRKA) in Lung Cancer

NTRK1 fusions in lung cancer are found in 3.3% of cases with adenocarcinoma histology (3 out of 91 patients; Vaishnavi et al. 2013). In two of three cases described, the patients were female with lung adenocarcinoma who had never smoked (Vaishnavi et al. 2013). The patients’ tumors tested negative for EGFR and KRAS mutations as well as ALK or ROS1 fusions (Vaishnavi et al. 2013).

Two different NTRK1 fusions have been described in non-small cell lung cancer using next-generation sequencing, MPRIP-NTRK1 and CD74-NTRK1 (Figure 1; Vaishnavi et al. 2013). Preclinical studies support the role of these fusions in TRKA autophosphorylation leading to oncogenic processes (Vaishnavi et al. 2013).

Clinically, the presence of an NTRK1 rearrangement is detected by fluorescence in situ hybridization (FISH) with an NTRK1 breakapart probe. FISH testing is not able to discern which particular NTRK1 fusion is found in a clinical sample.


ntrk1-fusions-nsclc.png

Figure 1
. Schematic representation of NTRK1 (TRKA) fusions found in lung cancer. ​

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Contributors: Christine M. Lovly, M.D., Ph.D., Robert C. Doebele, M.D., Ph.D.

Suggested Citation: Lovly, C., R. Doebele. 2014. NTRK1 (TRKA) in Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/ntrk1/ (Updated May 23).

Last Updated: May 23, 2014

NTRK1 (TRKA) Fusions in Lung Cancer

Properties
Location of mutation Chromosomal rearrangements involving the NTRK1 gene on chromosome 1
Frequency of NTRK1 fusion in lung adenocarcinoma 3.3% (Vaishnavi et al. 2013)
Implications for Targeted Therapeutics
Response to pan-TRK tyrosine kinase inhibitors Unknown at this timea
Response to FLT3/TRKA kinase inhibitors Unknown at this timeb
Response to ALK/MET/ROS1/TRKA tyrosine kinase inhibitors Unknown at this timec

NTRK1 rearrangements involve the kinase domain of the NTRK1 gene which includes 17 exons located on chromosome 1q21-22 (Alberti et al. 2003). The frequency of NTRK1 fusions in patients with adenocarcinoma histology is 3.3% of cases (3 out of 91 patients; Vaishnavi et al. 2013).

a In preclinical studies, cell lines expressing MPRIP-NTRK1 or CD74-NTRK1 were inhibited by ARRY-470, a TRKA/B/C inhibitor (Vaishnavi et al. 2013).

b In preclinical studies, cell lines expressing MPRIP-NTRK1 or CD74-NTRK1 were inhibited by lestaurtinib, a FLT3/TRKA inhibitor (Vaishnavi et al. 2013).

c A patient with non-small cell lung cancer harboring an MPRIP-NTRK1 fusion mutation was treated with crizotinib, which has activity against TRKA in addition to ALK, MET and ROS1 (Vaishnavi et al. 2013). The patient demonstrated a small radiographic decrease in tumor size but experienced disease progression after three months (Vaishnavi et al. 2013).​​

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Contributors: Christine M. Lovly, M.D., Ph.D., Robert C. Doebele, M.D., Ph.D.

Suggested Citation: Lovly, C., R. Doebele. 2014. NTRK1 (TRKA) Fusions in Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/ntrk1/315/ (Updated May 23).

Last Updated: May 23, 2014

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