TY - JOUR
T1 - Discovery and characterization of targetable NTRK point mutations in hematologic neoplasms
AU - Joshi, Sunil K.
AU - Qian, Kristin
AU - Bisson, William H.
AU - Watanabe-Smith, Kevin
AU - Huang, Ariane
AU - Bottomly, Daniel
AU - Traer, Elie
AU - Tyner, Jeffrey W.
AU - McWeeney, Shannon K.
AU - Davare, Monika A.
AU - Druker, Brian J.
AU - Tognon, Cristina E.
N1 - Funding Information:
This work was supported by the Howard Hughes Medical Institute, the Leukemia & Lymphoma Society, and National Institutes of Health, National Cancer Institute grant 1R01CA214428 (B.J.D.). B.J.D. was also supported by National Cancer Institute grants 1U01CA217862, 5U01CA214116, and 1U54CA224019. S.K.J. was supported by the Achievement Rewards for College Scientists (ARCS) Scholar Foundation, The Paul & Daisy Soros Fellowship, and National Cancer Institute grant 1F30CA239335-01. E.T. was supported by Leukemia & Lymphoma Society grant LLS SCOR 7005-11, Lamfrom funds, American Cancer Society grant MRSG-17-040-01-LIB, and National Cancer Institute grant 1U54CA224019. J.W.T. received V Foundation for Cancer Research and Gabrielle’s Angel Foundation for Cancer Research grants, and National Cancer Institute grants 1R01CA183947, 1U01CA217862, 1U54CA224019, and 3P30CA069533.
Funding Information:
The authors are extremely thankful to their patients for their time and precious tissue samples. The authors also thank the Oregon Health & Science University (OHSU) Massively Parallel Sequencing Shared Resource and Flow Cytometry Core for technical support, Nicola Long and Beth Wilmot for analytical support, and Stephen Kurtz for critical review of the manuscript. This work was supported by the Howard Hughes Medical Institute, the Leukemia & Lymphoma Society, and National Institutes of Health, National Cancer Institute grant 1R01CA214428 (B.J.D.). B.J.D. was also supported by National Cancer Institute grants 1U01CA217862, 5U01CA214116, and 1U54CA224019. S.K.J. was supported by the Achievement Rewards for College Scientists (ARCS) Scholar Foundation, The Paul & Daisy Soros Fellowship, and National Cancer Institute grant 1F30CA239335-01. E.T. was supported by Leukemia & Lymphoma Society grant LLS SCOR 7005-11, Lamfrom funds, American Cancer Society grant MRSG-17-040-01-LIB, and National Cancer Institute grant 1U54CA224019. J.W.T. received V Foundation for Cancer Research and Gabrielle's Angel Foundation for Cancer Research grants, and National Cancer Institute grants 1R01CA183947, 1U01CA217862, 1U54CA224019, and 3P30CA069533.
Publisher Copyright:
© 2020 by The American Society of Hematology
PY - 2020/6/11
Y1 - 2020/6/11
N2 - 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 under-explored 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.
AB - 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 under-explored 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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U2 - 10.1182/blood.2019003691
DO - 10.1182/blood.2019003691
M3 - Article
C2 - 32315394
AN - SCOPUS:85086354843
SN - 0006-4971
VL - 135
SP - 2159
EP - 2170
JO - Blood
JF - Blood
IS - 24
ER -