American Association for Cancer Research
15357163mct170419-sup-183045_4_supp_4355563_cyg2mx.pdf (609.59 kB)

Supplemental Figure 6 from Antitumor Activity of Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor, in ETV6-NTRK3–Positive Acute Myeloid Leukemia

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journal contribution
posted on 2023-04-03, 15:01 authored by Kristen M. Smith, Patrick C. Fagan, Elena Pomari, Giuseppe Germano, Chiara Frasson, Colin Walsh, Ian Silverman, Paolo Bonvini, Gang Li

Entrectinib was not toxic in zebrafish xenograft assay.



Activation of tropomyosin receptor kinase (TRK) family tyrosine kinases by chromosomal rearrangement has been shown to drive a wide range of solid tumors and hematologic malignancies. TRK fusions are actionable targets as evidenced by recent clinical trial results in solid tumors. Entrectinib (RXDX-101) is an investigational, orally available, CNS-active, highly potent, and selective kinase inhibitor against TRKA/B/C, ROS1, and ALK kinase activities. Here, we demonstrate that TRK kinase inhibition by entrectinib selectively targets preclinical models of TRK fusion–driven hematologic malignancies. In acute myelogenous leukemia (AML) cell lines with endogenous expression of the ETV6–NTRK3 fusion gene, entrectinib treatment blocked cell proliferation and induced apoptotic cell death in vitro with subnanomolar IC50 values. Phosphorylation of the ETV6–TRKC fusion protein and its downstream signaling effectors was inhibited by entrectinib treatment in a dose-dependent manner. In animal models, entrectinib treatment at clinically relevant doses resulted in tumor regression that was accompanied by elimination of residual cancer cells from the bone marrow. Our preclinical data demonstrate the potential of entrectinib as an effective treatment for patients with TRK fusion–driven AML and other hematologic malignancies. Mol Cancer Ther; 17(2); 455–63. ©2017 AACR.