Abstract 4835: Genetic determinants of mTOR inhibitor response in breast and endometrial cancer

Abstract

Abstract Background: Breast and endometrial cancers frequently harbour genetic aberrations that result in increased activation of the PI3K-AKT-mTOR signalling pathway including amplification and overexpression of receptor tyrosine kinases, activating PIK3CA mutations, and inactivating PTEN mutations or loss of PTEN function. Given the pivotal role of the PI3K-AKT-mTOR pathway in cancer cell growth and survival, inhibitors of several of its components are currently being tested in clinical trials. The aim of this study was to define the genetic determinants of mTOR inhibitor response in breast and endometrial cancer cells. Methods: A panel of 31 breast and 26 endometrial cancer cell lines was treated with serial dilutions of ‘rapalogs’ (i.e. allosteric inhibitors of mTOR complex 1 (mTORC1)) and mTOR kinase inhibitors targeting mTORC1 and mTORC2. Cell viability was determined using CellTiter Blue. PTEN protein levels and mutations in PTEN transcripts were assessed in all cell lines using western blotting and Sanger sequencing, respectively. PIK3CA mutations were assessed using Sanger sequencing in the breast cancer cells, and hot-spot mutations in PIK3CA and 18 additional oncogenes using the Sequenom OncoCarta Panel v1.0 in the endometrial cancer cells. Results: Response of breast cancer cells to both the rapalog everolimus and the mTOR kinase inhibitor PP242 was determined by the presence of activating PIK3CA mutations but not PTEN loss of function. In addition, PP242 treatment induced a more efficient response in HER2-amplified breast cancer cell lines, irrespective of the PIK3CA mutation status. By contrast, endometrial cancer cell lines not only harbouring mutations in PIK3CA but also in PTEN were sensitive to treatment with the rapalog temsirolimus. The mTOR kinase inhibitor AZD8055 induced a strong reduction in cell viability in all endometrial cancer cell lines tested. Conclusions: Our results suggest that response to mTOR inhibitors in breast and endometrial cancer cells may be determined by the presence of alterations affecting PIK3CA and PTEN. Our data further indicate, however, that the epistatic interactions between different components of the PI3K-AKT-mTOR pathway are distinct in cancers of the breast and endometrium. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4835. doi:1538-7445.AM2012-4835