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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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 7

In vivo modeling of RSK4 resistance in PDXs.

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In vivo modeling of RSK4 resistance in PDXs. (A) Western blot analyses o...
(A) Western blot analyses of PDX60 (high RSK) and PDX156 (low RSK). Tumor-derived extracts from 3 individual tumors were analyzed with the indicated antibodies. (B) Patient-derived xenograft assay with PDX156 (low RSK, left panel) and PDX 60 (high RSK, right panel). Mice were treated daily with BKM120 (27.5 mg/kg) or vehicle (mean ± SEM, n = 8). (C) Western blot analysis of PDX156 and PDX60 tumors treated with DMSO or BKM120. Tumor-derived extracts from 3 individual tumors were analyzed with the indicated antibodies. (D) Patient-derived xenograft assay with PDX60 tumor treated with DMSO, BKM120, MEK, or a combination (mean ± SEM, n = 8). (E) Western blot analysis of PDX tumors treated with DMSO, BKM120, MEK162, or a combination. Tumor-derived extracts were analyzed with the indicated antibodies. (F) Schematic overview of PI3K/mTOR and ERK/RSK pathways converging to regulate S6 phosphorylation and translation. Observations presented here support a model in which aberrant activation of the ERK/RSK signaling axis contributes to S6 phosphorylation, translation initiation, and resistance to PI3K/mTOR blockade.