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

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-...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2018-02, Vol.17 (2), p.455-463
Main Authors: Smith, Kristen M, Fagan, Patrick C, Pomari, Elena, Germano, Giuseppe, Frasson, Chiara, Walsh, Colin, Silverman, Ian, Bonvini, Paolo, Li, Gang
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Animal models
Anticancer properties
Antitumor activity
Apoptosis
Bone cancer
Bone marrow
Cancer
Cell death
Cell proliferation
Central nervous system
Enzyme inhibitors
Fusion protein
Gene expression
Inhibitors
Kinases
Leukemia
Myeloid leukemia
Phosphorylation
Signaling
Solid tumors
TrkA protein
Tropomyosin
Tumor cell lines
Tumors
Tyrosine
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Summary: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 fusion gene, entrectinib treatment blocked cell proliferation and induced apoptotic cell death with subnanomolar IC 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. .
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-17-0419