Abstract 4452: p90RSK mediates resistance to PI3K-pathway inhibitors in breast cancer.

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 they 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 uncover potential mechanisms of resistance to PI3K inhibitors and have identified several genes whose expression promotes survival under conditions of 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 an apoptotic response and upregulation of protein translation. The addition of MEK- or RSK-specific inhibitors can extinguish these resistance phenotypes, both in cells engineered to overexpress RSK and in breast cancer cells that have 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. Citation Format: Violeta Serra, Pieter JA Eichhorn, Celina Garcia-Garcia, Yasir Ibrahim, Ludmila Prudkin, Olga Rodriguez, Sara Marlow, Aleix Prat, William C. Hahn, Jose Baselga. p90RSK mediates resistance to PI3K-pathway inhibitors in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4452. doi:10.1158/1538-7445.AM2013-4452