Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies
Justin Taylor, … , Jae H. Park, Omar Abdel-Wahab
Justin Taylor, … , Jae H. Park, Omar Abdel-Wahab
Published June 19, 2018
Citation Information: J Clin Invest. 2018;128(9):3819-3825. https://doi.org/10.1172/JCI120787.
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Concise Communication Hematology Oncology

Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies

Abstract

Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. Although TRK fusions occur in fewer than 1% of all solid tumors, inhibition of TRK results in profound therapeutic responses, resulting in Breakthrough Therapy FDA approval of the TRK inhibitor larotrectinib for adult and pediatric patients with solid tumors, regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and the clinical effects of targeting TRK in hematologic malignancies are unknown. Here, through an evaluation for TRK fusions across more than 7,000 patients with hematologic malignancies, we identified TRK fusions in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), histiocytosis, multiple myeloma, and dendritic cell neoplasms. Although TRK fusions occurred in only 0.1% of patients (8 of 7,311 patients), they conferred responsiveness to TRK inhibition in vitro and in vivo in a patient-derived xenograft and a corresponding AML patient with ETV6-NTRK2 fusion. These data identify that despite their individual rarity, collectively, TRK fusions are present in a wide variety of hematologic malignancies and predict clinically significant therapeutic responses to TRK inhibition.

Authors

Justin Taylor, Dean Pavlick, Akihide Yoshimi, Christina Marcelus, Stephen S. Chung, Jaclyn F. Hechtman, Ryma Benayed, Emiliano Cocco, Benjamin H. Durham, Lillian Bitner, Daichi Inoue, Young Rock Chung, Kerry Mullaney, Justin M. Watts, Eli L. Diamond, Lee A. Albacker, Tariq I. Mughal, Kevin Ebata, Brian B. Tuch, Nora Ku, Maurizio Scaltriti, Mikhail Roshal, Maria Arcila, Siraj Ali, David M. Hyman, Jae H. Park, Omar Abdel-Wahab

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Figure 2

TRK fusions confer responsiveness to TRK inhibition in hematopoietic malignancies in vitro and in vivo.

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TRK fusions confer responsiveness to TRK inhibition in hematopoietic mal...
(A) Colony numbers derived from c-Kit+ murine bone marrow cells stably expressing the indicated constructs grown in increasing concentrations (0, 25, and 50 nM) of larotrectinib in methylcellulose. (B) Cell viability of IL-3–independent 32D cells expressing TRK fusions following 72 hours of larotrectinib or vehicle treatment. The IC50 is calculated from the slope of the log inhibitor versus response curve. (C) Schematic of creation and testing of larotrectinib in a PDX from a patient with AML with an ETV6-NTRK2 fusion. (D) Flow cytometric analysis of mouse versus human cell subsets (mCD45 versus hCD45) in BM of a PDX after larotrectinib or vehicle treatment. Each row represents a distinct individual mouse xenografted with the same patient sample; all percentages represent percentage of live mouse Ter119–negative (mTer119-negative) cells. (E) Anti-hCD45 immunohistochemical analysis in BM from PDX mice treated with vehicle or larotrectinib for 14 days (top row scale bar, 200 μm; bottom row scale bar, 50 μm). Each column represents a distinct individual mouse xenografted with the same patient sample. Error bars represent mean and SD from triplicate samples. Differences were calculated using a 2-sided Student’s t test and corrected for multiple testing using the Bonferroni method (*P < 0.0125).