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Updated: Oct 8, 2025
Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
NTRK point mutations and their functional consequences
Corey Rogers1, Jennifer J D Morrissette1, Robyn T Sussman1
1Department of Pathology and Laboratory Medicine, Division of Precision and Computational Diagnostics, University of Pennsylvania, 3020 Market Street, Suite 220, Philadelphia, PA 19104, USA.
Abstract:
The neurotrophic receptor tyrosine kinase (NTRK) family of genes, including NTRK1, NTRK2, and NTRK3, encodes membrane-bound receptors that normally regulate cell survival and differentiation upon binding of growth factors. Not surprisingly, mutations in these genes are known to contribute to the growth of a diverse number of cancers. With the recent FDA approval of two first-generation tyrosine-kinase inhibitors (TKIs) for adult and pediatric patients with solid tumors harboring NTRK gene fusions, much of the literature has focused on the biology behind these types of NTRK abnormalities; however, point mutations can also contribute to oncogenesis or resistance to TKI therapy, albeit at a lower frequency than fusions. This review focuses on NTRK gene mutations that are associated with resistance to directed therapies, mutations detected in the primary setting that confer increased oncogenic activity, and evidence that suggests that some of these variants may be treated using specific targeted therapies. Finally, this review focuses on the detection of point mutations, including the utility of cell-free DNA (cfDNA) for monitoring the acquisition of resistance mutations.
Insights
NTRK gene mutations, beyond fusions, can drive cancer growth and TKI resistance. This review explores these mutations, their oncogenic roles, and potential targeted therapies, including cfDNA monitoring.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Neurotrophic receptor tyrosine kinase (NTRK) genes (NTRK1, NTRK2, NTRK3) encode receptors crucial for cell survival and differentiation.
- Mutations in NTRK genes are implicated in various cancers.
- While NTRK gene fusions are well-studied, point mutations also contribute to oncogenesis and therapy resistance.
Purpose of the Study:
- To review NTRK gene mutations beyond fusions.
- To discuss mutations conferring oncogenic activity and TKI resistance.
- To explore targeted therapies and cfDNA for mutation detection.
Main Methods:
- Literature review of NTRK gene mutations.
- Analysis of oncogenic roles and resistance mechanisms.
- Evaluation of targeted therapy and cfDNA detection methods.
Main Results:
- NTRK point mutations can drive oncogenesis and confer resistance to tyrosine-kinase inhibitors (TKIs).
- Some NTRK variants may be treatable with specific targeted therapies.
- Cell-free DNA (cfDNA) shows utility in monitoring resistance mutations.
Conclusions:
- NTRK point mutations represent a significant area in cancer biology and targeted therapy.
- Understanding these mutations is crucial for effective cancer treatment strategies.
- cfDNA analysis offers a promising non-invasive approach for monitoring treatment response and resistance.
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