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. In our recent publication we have took 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 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. Our 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.
Violeta Serra1, Pieter J.A. Eichhorn2, Celina García-García1, Yasir H. Ibrahim1, Ludmila Prudkin3, Gertrudis Sánchez3, Olga Rodríguez1, Pilar Antón1, Josep-Lluís Parra4, Sara Marlow5, Maurizio Scaltriti6, Aleix Prat7, Joaquín Arribas4, William C. Hahn8,9, So Young Kim10, and José Baselga1,6
Authorship note: Violeta Serra and Pieter J.A. Eichhorn contributed equally to this work.
1Experimental Therapeutics, Vall d’Hebron Institute of Oncology, Barcelona, Spain.
2Cancer Science Institute of Singapore, National University of Singapore, Singapore.
3Molecular Pathology and 4Growth Factors Groups, Vall d’Hebron Institute of Oncology, Barcelona, Spain.
5Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
6Human Oncology and Pathogenesis Program and Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
7Translational Genomics Unit, Vall d’Hebron Institute of Oncology, Barcelona, Spain.
8Center for Cancer Genome Discovery, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
9Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
10Department of Molecular Genetics and Microbiology, Duke RNAi Screening Facility, Duke University Medical Center, Durham, North Carolina, USA.