NTRK

Neurotrophic tropomyosin receptor kinase (NTRK)

NTRK Biology

  • NTRK genes encode for tropomyosin receptor kinases (TRKs) that attach to cell membranes and are involved in normal nervous system development.1
  • Under normal circumstances, neurotrophins activate TRK receptors, which lead to downstream ERK signaling, cellular proliferation, and growth.1
  • This receptor family has 3 known members: TRKA, TRKB, and TRKC.2
  • Their respective endogenous ligands are nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3, 4, and 5.2
  • Other pathways implicated in broad NTRK signaling include mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT.3

Etiology and Epidemiology

  • NTRK gene fusions are a driver gene for tumorigenesis.4 Oncogenesis occurs via hybrid gene fusions that result in the rearrangement of NTRK sequences to attach to constitutively activated genes.1
  • The C-terminal of the NTRK gene fuses with an N-terminal target, which results in an overexpression of the kinase domain of kinase function by the chimeric protein.4,5
  • The presence of NTRK gene fusions in solid tumors is approximately 1% but is more prevalent in certain rare tumors.2 They are present in less than 1% of BTC, and the rarity of these oncogenes limits our ability to form precise incidence estimates.6

Testing for NTRK Gene Fusions

  • When to Test: Patients with unresectable or metastatic biliary tract cancers (BTCs) who are candidates for systemic therapy should receive comprehensive molecular profiling at diagnosis.
  • Available Testing Methods: Given the rarity of NTRK fusions, National Comprehensive Cancer Network guidelines recommend multigene next-generation sequencing (NGS), preferably using a transcriptome-based approach.6 While immunohistochemistry, fluorescence in situ hybridization (FISH), and reverse transcriptase–chain polymerase reaction have been used to detect NTRK fusions, these methods are not mentioned in the guidelines for BTC.2,5
  • Guideline Recommendations for Testing: NTRK gene fusions are found in multiple unresectable or metastatic biliary tract cancers including gallbladder malignancies, intrahepatic cholangiocarcinomas (CCAs), and extrahepatic CCAs.6 Testing for these gene fusions is recommended for these 3 types of biliary tract cancer (BTC).6

NTRK Targeted Therapy

  • Approved Agents: Two drugs have been approved by the FDA for the treatment of NTRK gene fusion–positive, unresectable or metastatic solid tumors including BTC.7,8 Larotrectinib was approved in 2018, and entrectinib was approved in 2019.7,8 Entrectinib is an inhibitor of TRKA, TRKB, and TRK3; larotrectinib is a selective pan-TRK inhibitor.2 Both have shown specificity to patients with NTRK gene fusions with little to no activity when fusions are absent.4,7,8 Both TRK inhibitors have a favorable safety profile with a 57% to 75% response rate in pretreated, NTRK-positive tumors.4,6-9
  • Mechanism of Action: Larotrectinib and entrectinib are tyrosine kinase inhibitors specifically targeting TRKA, TRKB, and TRKC, anaplastic lymphoma kinase (ALK), and the proto-oncogene tyrosine-protein kinase 1 (ROS1).7,8

Learn more about Entrectinib >

Learn more about Larotrectinib >

References

  1. Farha N, Dima D, Ullah F, Kamath S. Precision oncology targets in biliary tract cancer. Cancers. 2023;15(7):2105. doi:10.3390/cancers15072105
  2. Manea CA, Badiu DC, Ploscaru IC, et al. A review of NTRK fusions in cancer. Ann Med Surg (Lond). 2022;79:103893. doi:10.1016/j.amsu.2022.103893
  3. Okamura R, Boichard A, Kato S, Sicklick JK, Bazhenova L, Kurzrock R. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: Implications for NTRK-targeted therapeutics. JCO Precis Oncol. 2018;(2):1-20. doi:10.1200/PO.18.00183
  4. Lange A, Lo HW. Inhibiting TRK proteins in clinical cancer therapy. Cancers (Basel). 2018;10(4):105. doi:10.3390/cancers10040105
  5. Demols A, Rocq L, Perez-Casanova L, et al. A two-step diagnostic approach for NTRK gene fusion detection in biliary tract and pancreatic adenocarcinomas. Oncologist. 2023;28(7):e520-e525. doi:10.1093/oncolo/oyad075
  6. NCCN. Clinical Guidelines in Oncology. Pancreatic adenocarcinoma, version 1.2024. Accessed June 11, 2024. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  7. ROZLYTREK (entrectinib). Prescribing information. Genentech; 2019. Accessed May 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf
  8. VITRAKVI (larotrectinib). Prescribing information. Loxo Oncology; 2018. Accessed May 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211710s000lbl.pdf
  9. Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531-540. doi:10.1016/S1470-2045(19)30856-3