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Abstract B38: p90RSK mediates resistance to PI3K-pathway inhibitors in breast cancer

Publication ,  Journal Article
Eichhorn, PJA; Serra, V; Garcia-Garcia, C; Ibrahim, YH; Prudkin, L; Parra, J-L; Prat, A; Hahn, WC; Kim, SY; Baselga, J
Published in: Molecular Cancer Therapeutics
July 1, 2015

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 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. 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: Pieter J.A. Eichhorn, Violeta Serra, Celina Garcia-Garcia, Yasir H. Ibrahim, Lumilla Prudkin, Josep-Lluis Parra, Aleix Prat, William C. Hahn, So Young Kim, Jose Baselga. p90RSK mediates resistance to PI3K-pathway inhibitors in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B38.

Duke Scholars

Published In

Molecular Cancer Therapeutics

DOI

EISSN

1538-8514

ISSN

1535-7163

Publication Date

July 1, 2015

Volume

14

Issue

7_Supplement

Start / End Page

B38 / B38

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1115 Pharmacology and Pharmaceutical Sciences
  • 1112 Oncology and Carcinogenesis
 

Citation

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Eichhorn, P. J. A., Serra, V., Garcia-Garcia, C., Ibrahim, Y. H., Prudkin, L., Parra, J.-L., … Baselga, J. (2015). Abstract B38: p90RSK mediates resistance to PI3K-pathway inhibitors in breast cancer. Molecular Cancer Therapeutics, 14(7_Supplement), B38–B38. https://doi.org/10.1158/1538-8514.pi3k14-b38
Eichhorn, Pieter J. A., Violeta Serra, Celina Garcia-Garcia, Yasir H. Ibrahim, Lumilla Prudkin, Josep-Lluis Parra, Aleix Prat, William C. Hahn, So Young Kim, and Jose Baselga. “Abstract B38: p90RSK mediates resistance to PI3K-pathway inhibitors in breast cancer.” Molecular Cancer Therapeutics 14, no. 7_Supplement (July 1, 2015): B38–B38. https://doi.org/10.1158/1538-8514.pi3k14-b38.
Eichhorn PJA, Serra V, Garcia-Garcia C, Ibrahim YH, Prudkin L, Parra J-L, et al. Abstract B38: p90RSK mediates resistance to PI3K-pathway inhibitors in breast cancer. Molecular Cancer Therapeutics. 2015 Jul 1;14(7_Supplement):B38–B38.
Eichhorn, Pieter J. A., et al. “Abstract B38: p90RSK mediates resistance to PI3K-pathway inhibitors in breast cancer.” Molecular Cancer Therapeutics, vol. 14, no. 7_Supplement, American Association for Cancer Research (AACR), July 2015, pp. B38–B38. Crossref, doi:10.1158/1538-8514.pi3k14-b38.
Eichhorn PJA, Serra V, Garcia-Garcia C, Ibrahim YH, Prudkin L, Parra J-L, Prat A, Hahn WC, Kim SY, Baselga J. Abstract B38: p90RSK mediates resistance to PI3K-pathway inhibitors in breast cancer. Molecular Cancer Therapeutics. American Association for Cancer Research (AACR); 2015 Jul 1;14(7_Supplement):B38–B38.

Published In

Molecular Cancer Therapeutics

DOI

EISSN

1538-8514

ISSN

1535-7163

Publication Date

July 1, 2015

Volume

14

Issue

7_Supplement

Start / End Page

B38 / B38

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1115 Pharmacology and Pharmaceutical Sciences
  • 1112 Oncology and Carcinogenesis