Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer.

摘要: Metastatic breast cancer is an incurable disease and identification of novel therapeutic opportunities vital. Triple-negative (TNBC) frequently metastasizes high levels activated p90RSK (RSK), a downstream MEK-ERK1/2 effector, are found in TNBC. We demonstrate, using direct pharmacologic genetic inhibition RSK1/2, that these kinases contribute to the TNBC metastatic process vivo Kinase profiling showed RSK1 RSK2 predominant targeted by new inhibitor, which based on natural product SL0101. Further evidence for selectivity was provided observations silencing eliminated ability analogue further inhibit survival or proliferation cell line. In vivo, derivative as effective FDA-approved MEK inhibitor trametinib reducing establishment foci. Importantly, RSK1/2 did not result activation AKT, known limit efficacy inhibitors clinic. Our results demonstrate RSK major contributor program provide preclinical proof-of-concept SL0101 Mol Cancer Ther; 15(11); 2598-608. ©2016 AACR.