TRKing Down an Old Oncogene in a New Era of Targeted Therapy

摘要

ABSTRACT 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. INTRODUCTION The identification of dominant oncogenic mutations and our ability to specifically inhibit these genetic abnormalities with targeted inhibitors have altered the therapeutic approach for many patients with cancer, particularly those with non-small cell lung cancer (NSCLC). Activating point mutations, in-frame insertions/deletions, gene amplification, and gene rearrangements can serve as predictive biomarkers for oncogene-targeted therapies and thus help select patients that have a high likelihood of benefiting from a particular therapy. There are currently two well-established paradigms of this targeted therapy approach in NSCLC, both of which highlight the potential success of this strategy for other oncogene targets.