Project description:Activation of 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 with low nanomolar potency 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 myeloid 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 sub-nanomolar IC50 values. Phosphorylation of the ETV6-TRKC fusion protein, as well as phosphorylation of known TRKC downstream signaling effectors, was inhibited by entrectinib treatment in a dose-dependent manner. Sensitivity to entrectinib was dependent on expression of the ETV6-TRKC fusion protein. In xenograft models, entrectinib treatment at clinically relevant doses resulted in tumor regression, which 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 provide rationale for the clinical development of entrectinib in molecularly defined hematologic malignancies.

2018-07-05 | GSE100885 | GEO

Extraskeletal osteosarcoma harboring ETV6::NTRK3 fusion treated successfully with larotrectinib: a case study.

Project description: Not available

| S-EPMC12634677 | biostudies-literature

Characterization of a newly identified ETV6-NTRK3 fusion transcript in acute myeloid leukemia.

Project description: Not available

| S-EPMC3063188 | biostudies-literature

ETV6-NTRK3 induces aggressive acute lymphoblastic leukemia highly sensitive to selective TRK inhibition.

Project description: Not available

| S-EPMC6107883 | biostudies-literature

Complete response to larotrectinib treatment in a patient with papillary thyroid cancer harboring an <i>ETV6-NTRK3</i> gene fusion.

Project description: Not available