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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Serra, V; Eichhorn, PJA; García-García, C; Ibrahim, YH; Prudkin, L; Sánchez, G; Rodríguez, O; Antón, P; Parra, J-L; Marlow, S; Scaltriti, M; Pérez-Garcia, J; Prat, A; Arribas, J; Hahn, WC; Kim, SY; Baselga, J

Published Date

  • June 2013

Published In

Volume / Issue

  • 123 / 6

Start / End Page

  • 2551 - 2563

PubMed ID

  • 23635776

Pubmed Central ID

  • 23635776

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/JCI66343

Language

  • eng