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Ref Type Journal Article
PMID (32315394)
Authors Joshi SK, Qian K, Bisson WH, Watanabe-Smith K, Huang A, Bottomly D, Traer E, Tyner JW, McWeeney SK, Davare MA, Druker BJ, Tognon CE
Title Discovery and characterization of targetable NTRK point mutations in hematologic neoplasms.
Journal Vol Issue Date Pages Journal Short Title
Blood 135 24 2020 Jun 11 2159-2170 Blood
URL
Abstract Text Much of what is known about the neurotrophic receptor tyrosine kinase (NTRK) genes in cancer was revealed through 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 pan-Trk inhibitors larotrectinib and entrectinib in clinical trials led to their accelerated, tissue-agnostic US Food and Drug Administration (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 identified via deep sequencing of 185 patients with hematological malignancies. Ten patients contained a point mutation in NTRK2 or NTRK3; among these, we identified 9 unique point mutations. Of these 9 mutations, 4 were oncogenic (NTRK2A203T, NTRK2R458G, NTRK3E176D, and NTRK3L449F), determined via cytokine-independent cellular assays. Our data demonstrate that these mutations have transformative potential to promote downstream survival signaling and leukemogenesis. Specifically, the 3 mutations located within extracellular (ie, NTRK2A203T and NTRK3E176D) and transmembrane (ie, NTRK3L449F) domains increased receptor dimerization and cell-surface abundance. The fourth mutation, NTRK2R458G, residing in the juxtamembrane domain, activates TrkB via noncanonical mechanisms that may involve altered interactions between the mutant receptor and lipids in the surrounding environment. Importantly, these 4 activating mutations can be clinically targeted using entrectinib. Our findings contribute to ongoing efforts to define the mutational landscape driving hematological malignancies and underscore the utility of FDA-approved Trk inhibitors for patients with aggressive Trk-driven leukemias.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
NTRK2 A203T missense gain of function NTRK2 A203T lies within Ig-like C2-type domain 1 of the Ntrk2 protein (UniProt.org). A203T results in increased cell surface expression and receptor dimerization of Ntrk2, and leads to increased phosphorylation of Ntrk2, Akt, and Erk, and IL3-independent growth in culture (PMID: 32315394).
NTRK2 H245Y missense no effect - predicted NTRK2 H245Y lies within Ig-like C2-type domain 1 of the Ntrk2 protein (UniProt.org). H245Y does not induce IL-3 independent growth in cultured cells (PMID: 32315394), and therefore, is predicted to have no effect on Ntrk2 protein function.
NTRK2 R458G missense gain of function NTRK2 R458G lies within the cytoplasmic domain of the Ntrk2 protein (UniProt.org). R458G results in cell surface expression and receptor dimerization similar to wild-type Ntrk2 but leads to increased phosphorylation of Ntrk2, Akt, and Erk, and IL3-independent growth in culture (PMID: 32315394).
NTRK2 S167Y missense no effect - predicted NTRK2 S167Y lies within the LRRCT domain of the Ntrk2 protein (UniProt.org). S167Y does not induce IL-3 independent growth in cultured cells (PMID: 32315394), and therefore, is predicted to have no effect on Ntrk2 protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NTRK2 A203T hematologic cancer sensitive Foretinib Preclinical - Cell culture Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of transformed cells expressing NTRK2 A203T in culture (PMID: 32315394). 32315394
NTRK2 A203T hematologic cancer sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited viability of transformed cells expressing NTRK2 A203T in culture (PMID: 32315394). 32315394
NTRK2 R458G hematologic cancer sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited viability of transformed cells expressing NTRK2 R458G in culture (PMID: 32315394). 32315394
NTRK2 R458G hematologic cancer sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited viability of transformed cells expressing NTRK2 R458G in culture (PMID: 32315394). 32315394
NTRK2 A203T hematologic cancer sensitive Larotrectinib Preclinical - Cell culture Actionable In a preclinical study, Vitrakvi (larotrectinib) inhibited viability of transformed cells expressing NTRK2 A203T in culture (PMID: 32315394). 32315394
NTRK2 R458G hematologic cancer sensitive Foretinib Preclinical - Cell culture Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of transformed cells expressing NTRK2 R458G in culture (PMID: 32315394). 32315394
NTRK2 A203T hematologic cancer sensitive Entrectinib Preclinical - Cell culture Actionable In a preclinical study, Rozlytrek (entrectinib) decreased Ntrk2 phosphorylation and viability and increased apoptosis in a transformed cell line expressing NTRK2 A203T in culture (PMID: 32315394). 32315394
NTRK2 R458G hematologic cancer sensitive Cabozantinib Preclinical - Cell culture Actionable In a preclinical study, Cometriq (Cabometyx, cabozantinib) inhibited viability of transformed cells expressing NTRK2 R458G in culture (PMID: 32315394). 32315394
NTRK2 R458G hematologic cancer sensitive Larotrectinib Preclinical - Cell culture Actionable In a preclinical study, Vitrakvi (larotrectinib) inhibited viability of transformed cells expressing NTRK2 R458G in culture (PMID: 32315394). 32315394
NTRK2 R458G hematologic cancer sensitive Entrectinib Preclinical - Cell culture Actionable In a preclinical study, Rozlytrek (entrectinib) decreased Ntrk2 phosphorylation and viability and increased apoptosis in a transformed cell line expressing NTRK2 R458G in culture (PMID: 32315394). 32315394
NTRK2 A203T hematologic cancer sensitive Cabozantinib Preclinical - Cell culture Actionable In a preclinical study, Cometriq (Cabometyx, cabozantinib) inhibited viability of transformed cells expressing NTRK2 A203T in culture (PMID: 32315394). 32315394
NTRK2 A203T hematologic cancer sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited viability of transformed cells expressing NTRK2 A203T in culture (PMID: 32315394). 32315394
NTRK2 A203T hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib (CP-868596) inhibited viability of transformed cells expressing NTRK2 A203T in culture (PMID: 32315394). 32315394
NTRK2 R458G hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib (CP-868596) inhibited viability of transformed cells expressing NTRK2 R458G in culture (PMID: 32315394). 32315394