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

Ludwik KA, Campbell JP, Li M, Li Y, Sandusky ZM, Pasic L, Sowder ME, Brenin DR, Pietenpol JA, O'Doherty GA, Lannigan DA
Mol Cancer Ther. 2016 15 (11): 2598-2608

PMID: 27528706 · PMCID: PMC5807013 · DOI:10.1158/1535-7163.MCT-16-0106

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

©2016 American Association for Cancer Research.

MeSH Terms (22)

Animals Antineoplastic Agents Benzopyrans Cell Line, Tumor Cell Movement Cell Proliferation Cell Survival Disease Models, Animal Dose-Response Relationship, Drug Enzyme Activation Female Gene Silencing Humans Mice Monosaccharides Neoplasm Metastasis Protein Kinase Inhibitors Proto-Oncogene Proteins c-akt Ribosomal Protein S6 Kinases, 90-kDa Triple Negative Breast Neoplasms Tumor Burden Xenograft Model Antitumor Assays

Connections (4)

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