Abstract A29: PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

• Published in: Molecular cancer therapeutics 2013-11, Vol.12 (11_Supplement), p.A29-A29
• Main Authors: Ebi, Hiromichi, Costa, Carlotta, Faber, Anthony, Juric, Dejan, Della Pelle, Patricia, Song, Youngchul, Yano, Seiji, Mino-Kenudson, Mari, Benes, Cyril H., Engelman, Jeffrey A.
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-13-A29

The phosphatidylinositol 3-kinase (PI3K) pathway is genetically activated in excess of 70% of breast cancers, often throughPIK3CA mutation and HER2 amplification. Previous studies with PI3K inhibitors have suggested enhanced sensitivity in this subset of breast cancers, however, the mechanism underlying this sensitivity is mainly unknown. In this study, we investigated the signaling consequences of PI3K inhibition in PIK3CA mutant and HER2 amplified breast cancers, and unexpectedly observed suppression of ERK signaling in these cancers. In contrast to PI3K inhibitors, AKT inhibitors failed to block MEK/ERK signaling and to induce sustained apoptosis, suggesting that a different PI(3,4,5)P3-dependent pathway regulated ERK. We determined that suppression of ERK was due to loss of active Rac1, which led to suppression of PAK/c-RAF/MEK/ERK signaling. Expression of a constitutively active form of Rac1 abrogated the capacity for PI3K inhibitors to inhibit ERK, induce apoptosis, and have anti-tumor activity in vivo. Further studies identified P-Rex1 as the PI(3,4,5)P3-dependent guanine exchange factor for Rac1 responsible for regulation of the Rac1/PAK/c-RAF/MEK/ERK pathway in these breast cancer cells. Furthermore, the expression level of P-Rex1 in these breast cancer cells predicted for capacity for PI3K inhibitors to suppress ERK signaling and correlated with sensitivity to PI3K inhibitors. Thus, PI3K inhibitors have enhanced sensitivity in PIK3CA mutant and HER2 amplified breast cancers where PI3K inhibition downregulates both the AKT and Rac1/ERK pathways. In addition, P-Rex1 may serve as a biomarker to predict response to single-agent PI3K inhibitors within this subset of breast cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A29. Citation Format: Hiromichi Ebi, Carlotta Costa, Anthony Faber, Dejan Juric, Patricia Della Pelle, Youngchul Song, Seiji Yano, Mari Mino-Kenudson, Cyril H. Benes, Jeffrey A. Engelman. PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A29.