We identified four oncogenic NTRK point mutations in patients with hematologic neoplasms that are amenable to FDA-approved Trk inhibitors.
Much of what is known about the neurotrophic receptor tyrosine kinase (NTRK) genes in cancer is through the identification and characterization of activating Trk fusions across many tumor types. A resurgence of interest in these receptors has emerged owing to the realization that they are promising therapeutic targets. The remarkable efficacy of the pan-Trk inhibitors, larotrectinib and entrectinib, in clinical trials led to their accelerated, tissue agnostic FDA approval for adult and pediatric patients with Trk-driven solid tumors. Despite our enhanced understanding of Trk biology in solid tumors, the importance of Trk signaling in hematological malignancies is underexplored and warrants further investigation. Herein, we describe mutations in NTRK2 and NTRK3 that were identified via deep sequencing of 185 patients with hematological malignancies. Ten patients contained a point mutation in NTRK2 or NTRK3. Among these patients, we identified nine unique point mutations. Of these nine mutations, four were oncogenic-NTRK2A203T, NTRK2R458G, NTRK3E176D, and NTRK3L449F-as determined via cytokine-independent cellular assays. Our data demonstrate that these mutations have transformative potential to promote downstream survival signaling and leukemogenesis. Specifically, the three mutations located within the extracellular (i.e., NTRK2A203T and NTRK3E176D) and transmembrane (i.e., NTRK3L449F) domains increased receptor dimerization and cell-surface abundance. The fourth mutation, NTRK2R458G, residing in the juxtamembrane domain, activates TrkB via non-canonical mechanisms that may involve altered interactions between the mutant receptor and lipids in the surrounding environment. Importantly, these four activating mutations can be clinically targeted using entrectinib. Our findings contribute to ongoing efforts focused on defining the mutational landscape that drives hematological malignancies and underscore the utility of FDA-approved Trk inhibitors for patients with aggressive Trk-driven leukemias.