NTRK
Neurotrophic-tropomyosin receptor tyrosine kinase (NTRK)
NTRK Biology
The neurotrophic-tropomyosin receptor tyrosine kinase 1 (NTRK1), NTRK2, and NTKR3 genes encode for proteins TRKA, TRKB, and TRKC, respectively.1,2 NTRK proteins localize to cell membranes, and their endogenous ligands are neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3, neurotrophin-4, and neurotrophin-5.1–3 NTRK gene activation activates downstream signaling pathways RAS-RAF-MEK-ERK, phospholipase C, and phosphatidylinositol 3 kinase (PI3K).1–3
The NTRK proteins are involved in the growth and proliferation of neural cells in particular, and gene fusions can induce tumorigenesis in neural and non-neural cell cancers.1 When oncogenic, NTRK gene fusions are drivers for tumorigenesis and lead to constitutively active downstream signaling of various growth pathways.1,4
The rarity of NTRK gene fusions in CRC makes it challenging to elucidate clinicopathological characteristics. In a 2022 study, researchers analyzed a cohort of 16 patients with NTRK+ colorectal cancer (CRC) and found that of the three genes, NTRK1 rearrangements were the most common, and TPM3 was the most common fusion partner in introns 7-11.5 NTRK+ CRC variants were more likely to have microsatellite instability.5
NTRK Testing
NTRK gene fusions are prevalent in approximately 1% of solid tumors but are even more rare in colorectal cancer (0.35-0.7%).2,4–6 Testing should be included as part of a broader molecular profiling but is included in current guidelines because targeted TRK inhibitors are available and approved to treat CRC solid tumors.4 Guidelines endorse using multiple testing methodologies, depending on the accessibility of assays and available testing material.4 Feasible testing methods include immunohistochemistry (ICH), fluorescence in situ hybridization (FISH), DNA-based next-generation sequencing, and RNA-based NGS.2,4 The ideal approach appears to be RNA-based NGS because of the higher rates of false positives and lack of evidence of functional transcription present in other methods.4
NTRK Targeted Therapy
There are currently two treatment options for unresectable or metastatic solid tumors with NTRK gene fusions: larotrectinib and entrectinib.4,7,8 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 These targeted therapies are only appropriate for a small subset of CRC patients but offer an additional option with an attractive safety profile and an overall response rate of 57-79%.4,7,8
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References
1. 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 Precision Oncology. 2018;(2):1-20. doi:10.1200/PO.18.00183
2. Manea CA, Badiu DC, Ploscaru IC, et al. A review of NTRK fusions in cancer. Annals of Medicine & Surgery. 2022;79. doi:10.1016/j.amsu.2022.103893
3. Solomon JP, Hechtman JF. Detection of NTRK Fusions: Merits and Limitations of Current Diagnostic Platforms. Cancer Research. 2019;79(13):3163-3168. doi:10.1158/0008-5472.CAN-19-0372
4. National Comprehensive Cancer Network. NCCN guidelines version 1.2024: Colon Cancer. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
5. Wang H, Li Z, Ou Q, et al. NTRK fusion positive colorectal cancer is a unique subset of CRC with high TMB and microsatellite instability. Cancer Medicine. 2022;11(13):2541-2549. doi:10.1002/cam4.4561
6. Cocco E, Benhamida J, Middha S, et al. Colorectal Carcinomas Containing Hypermethylated MLH1 Promoter and Wild-Type BRAF/KRAS Are Enriched for Targetable Kinase Fusions. Cancer Research. 2019;79(6):1047-1053. doi:10.1158/0008-5472.CAN-18-3126
7. Vitraki (Larotrectinib) [Package Insert]. Loxo Oncology; 2018.
8. Rozlytrek (Entrectinib) [Package Insert]. Genentech; 2019.
9. FDA approves larotrectinib for solid tumors with NTRK gene fusions | FDA. Accessed March 18, 2024. https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions
10. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448
11. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC | FDA. Accessed March 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc
12. Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) Tumors: Pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Annals of Oncology. 2018;29:viii713. doi:10.1093/annonc/mdy424.017