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TRKing down an old oncogene in a new era of targeted therapy
Aria Vaishnavi1, Anh T Le1, Robert C Doebele2
1Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
Unlabelled:
The use of high-throughput next-generation sequencing techniques in multiple tumor types during the last few years has identified NTRK1, 2, and 3 gene rearrangements encoding novel oncogenic fusions in 19 different tumor types to date. These recent developments have led us to revisit an old oncogene, Trk (originally identified as OncD), which encodes the TPM3-NTRK1 gene fusion and was one of the first transforming chromosomal rearrangements identified 32 years ago. However, no drug has yet been approved by the FDA for cancers harboring this oncogene. This review will discuss the biology of the TRK family of receptors, their role in human cancer, the types of oncogenic alterations, and drugs that are currently in development for this family of oncogene targets.
Significance:
Precision oncology approaches have accelerated recently due to advancements in our ability to detect oncogenic mutations in tumor samples. Oncogenic alterations, most commonly gene fusions, have now been detected for the genes encoding the TRKA, TRKB, and TRKC receptor tyrosine kinases across multiple tumor types. The scientific rationale for the targeting of the TRK oncogene family will be discussed here.
Insights
Recent advances in next-generation sequencing have identified NTRK gene fusions in various cancers. This review explores TRK receptor biology, oncogenic alterations, and targeted therapies for TRK-driven tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- High-throughput sequencing identified NTRK1, 2, and 3 gene rearrangements in 19 tumor types.
- Trk (OncD), encoding the TPM3-NTRK1 fusion, was one of the first identified transforming chromosomal rearrangements.
- No FDA-approved drugs currently exist for cancers with this oncogene.
Purpose of the Study:
- To review the biology of the TRK family of receptors.
- To discuss their role in human cancer and oncogenic alterations.
- To examine drugs in development for TRK oncogene targets.
Main Methods:
- Review of scientific literature on TRK receptor tyrosine kinases.
- Analysis of next-generation sequencing data identifying NTRK gene fusions.
- Discussion of current drug development pipelines for TRK-targeted therapies.
Main Results:
- NTRK gene fusions encoding oncogenic TRK fusions have been identified in 19 distinct tumor types.
- TRKA, TRKB, and TRKC receptor tyrosine kinases are implicated in various cancers.
- Precision oncology has accelerated the detection of these oncogenic alterations.
Conclusions:
- TRK receptor tyrosine kinases are crucial oncogenic drivers across multiple tumor types.
- Gene fusions involving NTRK genes represent significant targets for cancer therapy.
- Targeting the TRK oncogene family holds promise for precision oncology.
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