NTRK1/2/3: biology, detection and therapy
M. Bungaro, Edoardo Garbo
Abstract
Abstract: The tropomyosin receptor kinase (TRK) receptor family comprises 3 transmembrane proteins named TrkA, TrkB, and TrkC, which are encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These tyrosine kinase receptors are physiologically expressed in human neuronal tissue and play essential roles in nervous system development and function. Gene fusions involving NTRK genes lead to transcription of constitutively active TRK proteins and drive oncogenesis in a broad range of different tumor types, including lung cancer. NTRK gene fusions represent an infrequent molecular alteration: in non-small cell lung cancer (NSCLC) they have been found in 0.1–0.2% of cases. However, these genetic alterations have recently become the subject of clinical interest as therapeutic targets. Because of the rarity of NTRK gene fusions in solid tumors and the complexity of fusion patterns, detection of these molecular alterations is complicated. However, screening cancer patients for NTRK fusions is critical in the clinical practice of precision cancer medicine, given the important therapeutic options currently available. There are several methods of detection, including immunohistochemistry, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, and next-generation sequencing (DNA- and/or RNA-based), each of which has pros and cons. Major regulatory agencies provide recommendations on the optimal ways to detect NTRK fusions and the prescription of related targeted drugs, but these are subject to heterogeneity around the world. The first generation of selective TRK inhibitors, larotrectinib and entrectinib, have been studied in phase 1/2 clinical trials in adult and pediatric solid tumors, and results have demonstrated high and durable response rates and generally good tolerability. The approval of larotrectinib and entrectinib by U.S. and European regulatory agents for any NTRK fusion-positive cancer was a major breakthrough in precision medicine. This review aims to describe the prevalence and role of NTRK fusions in the biology of NSCLC and to summarize the detection methods and available treatment data.