RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer
Violeta Serra, … , So Young Kim, José Baselga
Violeta Serra, … , So Young Kim, José Baselga
Published May 1, 2013
Citation Information: J Clin Invest. 2013;123(6):2551-2563. https://doi.org/10.1172/JCI66343.
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Research Article Oncology

RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer

Abstract

The PI3K signaling pathway regulates diverse cellular processes, including proliferation, survival, and metabolism, and is aberrantly activated in human cancer. As such, numerous compounds targeting the PI3K pathway are currently being clinically evaluated for the treatment of cancer, and several have shown some early indications of efficacy in breast cancer. However, resistance against these agents, both de novo and acquired, may ultimately limit the efficacy of these compounds. Here, we have taken a systematic functional approach to uncovering potential mechanisms of resistance to PI3K inhibitors and have identified several genes whose expression promotes survival under conditions of PI3K/mammalian target of rapamycin (PI3K/mTOR) blockade, including the ribosomal S6 kinases RPS6KA2 (RSK3) and RPS6KA6 (RSK4). We demonstrate that overexpression of RSK3 or RSK4 supports proliferation upon PI3K inhibition both in vitro and in vivo, in part through the attenuation of the apoptotic response and upregulation of protein translation. Notably, the addition of MEK- or RSK-specific inhibitors can overcome these resistance phenotypes, both in breast cancer cell lines and patient-derived xenograft models with elevated levels of RSK activity. These observations provide a strong rationale for the combined use of RSK and PI3K pathway inhibitors to elicit favorable responses in breast cancer patients with activated RSK.

Authors

Violeta Serra, Pieter J.A. Eichhorn, Celina García-García, Yasir H. Ibrahim, Ludmila Prudkin, Gertrudis Sánchez, Olga Rodríguez, Pilar Antón, Josep-Lluís Parra, Sara Marlow, Maurizio Scaltriti, José Pérez-Garcia, Aleix Prat, Joaquín Arribas, William C. Hahn, So Young Kim, José Baselga

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Figure 4

Reduced suppression of translation by PI3K inhibitors in RSK-overexpressing cells.

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Reduced suppression of translation by PI3K inhibitors in RSK-overexpress...
(A) MCF7 cells stably expressing GFP, AKT1, RSK3, or RSK4 were treated with BEZ235 (100 nM), BKM120 (1 μM), or pp242 (1 μM) for 24 hours. The levels of the indicated proteins were determined by immunoblotting. V5-tagged proteins were run on the same blot, but bands were noncontiguous due to differences in protein size. (B) MCF7 cells overexpressing RSK1, RSK2, RSK3, and RSK4 were treated with BEZ235 (100 nM) for 24 hours. The levels of the indicated proteins were determined by immunoblotting. (C) Proliferation of breast cancer cells treated with BEZ235 (100 nM) for 24 hours, assessed by CellTiter-Glo. Bars represent relative proliferation compared with untreated controls (mean ± SD of 3 independent experiments). (D) MCF7 cells overexpressing RSK4 were treated for 24 hours with indicated PI3K inhibitors prior to labeling new protein synthesis with 35S. Newly synthesized proteins were separated by SDS-PAGE, transferred to nitrocellulose, and visualized by autoradiography. (E) Quantification of newly synthesized protein (mean ± SD of 3 independent experiments).