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

Abstract

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 RSK, a downstream MEK-ERK1/2 effector, are found in TNBC. We demonstrate using direct pharmacological and genetic inhibition of RSK1/2 that these kinases contribute to the TNBC metastatic process in vivo. Kinase profiling demonstrated 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.

RSK1 promotes murine breast cancer growth and metastasis

“…Silencing of RSK1 reduced the number of metastatic foci to the similar extend as shown in our study. Furthermore, the level of activated RSKs was higher in TNBC tumors than in non-transformed mammary tissue [18]. Additionally, it was demonstrated that growth and migration of MDA-MB-231 TNBC cells, contrary to ER/PR-positive MCF7 cells, depended on both RSK1 and RSK2 activity [26].…”

“…Despite the continuous research in the field, functions of the RSK isoforms are still not well understood. Several authors have suggested that RSK1 plays an important role in TNBC, in particular in regulating cell motility and invasiveness [16][17][18]; however, the significance of RSK1 for the regulation of TNBC metastasis has never been investigated. Therefore, we examined for the first time an involvement of RSK1 in the regulation of TNBC growth and progression in an animal model which exhibits similar metastatic pattern to that of human disease.…”

ERα-Mediated Nuclear Sequestration of RSK2 Is Required for ER+ Breast Cancer Tumorigenesis

“…For two passages (every 9 days) spheres were dissociated with 1Â trypsin and equal number of cells from WT and NLS-RSK2 spheres were replated. Alternatively, p0 spheres (day 9) were transduced with GFP-luciferase and after 3 days the linearity of the bioluminescence signal was tested (15).…”

“…Indirect and direct fluorescence samples were stained as described (15,18) and an overview is provided in the Supplementary Data.…”

“…The kinase domains of the four members that comprise the RSK family are very similar but family members appear to have both redundant and separate contributions to development, homeostasis, and disease etiologies (6,7). RSK controls several oncogenic processes, including proliferation, viability, and motility and, therefore, has accordingly been implicated in the etiology of numerous cancers including breast (8)(9)(10)(11)(12)(13)(14)(15)(16). However, despite detailed knowledge on RSK oncogenic functions, the mechanistic rationale that underpins the correla-tion of active RSK with endocrine-based responsiveness in ER þ breast cancer remains an enigma.…”