Image by Lance Liotta
AML cells
WASHINGTON, DC—Preclinical data suggest a novel tyrosine kinase inhibitor (TKI) may be an effective treatment for patients with NTRK-rearranged acute myeloid leukemia (AML).
Entrectinib is a TKI targeting tumors that harbor TRK, ROS1, or ALK fusions.
Researchers found that entrectinib inhibited cell proliferation in NTRK-rearranged AML cell lines.
In mouse models of NTRK-rearranged AML, entrectinib induced tumor regression and eliminated residual AML cells from the bone marrow.
These results were presented at the AACR Annual Meeting 2017 (abstract 5158). The research was conducted by employees of Ignyta, Inc., the company developing entrectinib.
The researchers first tested entrectinib in AML cell lines. They observed “potent” anti-proliferative activity in a pair of NTRK-fusion-positive AML cell lines, IMS-M2 and M0-91.
Entrectinib inhibited TRK signaling and induced cell-cycle arrest in these cell lines. The TKI also induced both caspase 3-dependent apoptosis and PARP cleavage in a dose- and time-dependent manner.
However, entrectinib showed minimal activity against an NTRK-fusion-negative AML cell line, Kasumi-1.
The researchers also tested entrectinib in mouse models of NTRK-fusion-driven AML.
The TKI induced tumor regression in both IMS-M2 and M0-91 models, and the drug eliminated leukemic cells in the bone marrow.
The researchers said these results provide rationale for the clinical development of entrectinib in molecularly defined hematologic malignancies.
Entrectinib is currently being studied in a phase 2 trial of solid tumor malignancies.
