Analysis of <i>NTRK</i> Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics.

Abstract

Fusions that involve neurotrophic-tropomyosin receptor kinase (<i>NTRK</i>) genes are known drivers of oncogenesis. Therapies that target these ultra-rare, constitutionally active <i>NTRK</i> fusions have been remarkably effective. Herein, we analyze the prevalence of the full array of <i>NTRK</i> alterations-fusions, mutations, copy number alterations, and increased transcript expression-in diverse adult and pediatric tumor types to understand the landscape of <i>NTRK</i> aberrations in cancer. We assessed 13,467 samples available from The Cancer Genome Atlas (adult tumors) and the St Jude PeCan database (pediatric tumors) for the prevalence of <i>NTRK</i> fusions, as well as associated genomic and transcriptomic co-aberrations in different tumor types. <i>NTRK</i> fusions were observed in 0.31% of adult tumors and in 0.34% of pediatric tumors. The most common gene partners were <i>NTRK3</i> (0.16% of adult tumors) followed by <i>NTRK1</i> (0.14% of pediatric tumors). <i>NTRK</i> fusions were found more commonly in pediatric melanoma (11.1% of samples), pediatric glioma (3.97%), and adult thyroid cancers (2.34%). Additional genomic and transcriptomic <i>NTRK</i> alterations- mutation, amplification, and mRNA overexpression-occurred in 14.2% of samples, whereas the frequency of alterations that implicated <i>NTRK</i> ligands and the <i>NTRK</i> co-receptor (p75NTR) ranged from 3.8% to 5.4%. Among 31 adult samples carrying <i>NTRK</i> fusions, co-alterations occurred often and usually involved the downstream phosphoinositide-3-kinase signaling pathway, cell-cycle machinery, other tyrosine-kinase receptors, and mitogen-activated protein kinase signals. Whereas <i>NTRK</i> fusions are exceedingly rare, other <i>NTRK</i> abnormalities affect 14% of patients with cancer. Affecting these alterations has not yet been achievable in cancer. Genomic co-alterations occur frequently with <i>NTRK</i> fusions, but it is not known if co-targeting them can attenuate primary or secondary resistance to NTRK inhibitors.