Abstract 1540: Targeting PI3K/mTOR inhibitor induced survival programs abrogates resistance to cell death in ECM-attached cancer cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-04, Vol.71 (8_Supplement), p.1540-1540
• Main Authors: Muranen, Taru E., Morales, Fabiana, Selfors, Laura, Worster, Devin, Albeck, John, Gao, Sizhen, Iwanicki, Marcin, Mills, Gordon, Brugge, Joan S.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-1540

Alterations in the PI3-kinase pathway are common in breast, endometrial, and ovarian cancer and are thought to serve as major drivers of proliferation and survival. Multiple compounds targeting PI3-kinase pathway are currently in clinical trials. We have examined the sensitivity of ovarian and breast tumor cell lines to dual PI3K/mTOR inhibitors in 3D tumor spheroid assays. Interestingly, tumor cells in the center of the spheroids that are not attached to matrix are generally highly sensitive to NVP-BEZ235 and undergo apoptosis, whereas those in contact with matrix are highly resistant. In order to understand the basis for the differential sensitivity to NVP-BEZ235 and to identify candidate targets to abrogate this resistance, we performed reverse phase protein array of tumor spheroids treated with NVP-BEZ235. While NVP-BEZ235 inhibited known downstream targets of PI3K/mTOR, there was significant up-regulation of multiple proteins known to regulate cell survival including IGF1R, p-EGFR and several Bcl-2 family members. This response raised the question whether combined inhibition of PI3K/mTOR and any of the induced proteins would sensitize the matrix-attached cells. Interestingly, inhibition of Bcl-2 by ABT737 caused widespread apoptosis in the 3D structures, but only in combination with NVP-BEZ235. In addition, matrix-resistance was abrogated by combined treatment with NVP-BEZ235 and inhibition of EGFR or knockdown IGF1R. These results indicate that inhibition of PI3K/mTOR leads to induction of several protective pathways and that suppression of these pathways can significantly enhance sensitivity to PI3K/mTOR targeted therapies. In addition, these studies suggest a rational approach to the development of combination therapies – that is, through identification of drug-induced survival pathways and targeting these pathways in combination. Our current efforts center on investigating the mechanisms of PI3K/mTOR inhibition resistance and addressing the efficacy of the dual treatment in preclinical models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1540. doi:10.1158/1538-7445.AM2011-1540