PUBLICATION

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

Authors
Smith, K.M., Fagan, P.C., Pomari, E., Germano, G., Frasson, C., Walsh, C., Silverman, I., Bonvini, P., Li, G.
ID
ZDB-PUB-190321-17
Date
2018
Source
Molecular cancer therapeutics   17: 455-463 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Animals
  • Benzamides/pharmacology
  • Benzamides/therapeutic use*
  • Cell Line, Tumor
  • Female
  • Humans
  • Indazoles/pharmacology
  • Indazoles/therapeutic use*
  • Leukemia, Myeloid, Acute/drug therapy*
  • Leukemia, Myeloid, Acute/genetics
  • Leukemia, Myeloid, Acute/pathology
  • Mice
  • Mice, SCID
  • Oncogene Proteins, Fusion/genetics*
  • Protein Kinase Inhibitors/pharmacology
  • Protein Kinase Inhibitors/therapeutic use*
  • Protein-Tyrosine Kinases/genetics*
  • Proto-Oncogene Proteins/genetics*
  • Zebrafish
PubMed
29237803 Full text @ Mol. Cancer Ther.
Abstract
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.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes