Abstract 4472: PI3K pathway dependencies in endometrioid endometrial cancer.

Abstract

Abstract Background: Endometrioid endometrial cancers (EECs) frequently harbor coexisting mutations in PI3K pathway genes, including PTEN, PIK3CA, PIK3R1, and KRAS. We sought to determine the genetic determinants of PI3K pathway inhibitor response in EEC cells, and whether PTEN-mutant EEC cells rely on p110β signaling for survival. Methods: Twenty-four human EEC cell lines were characterized for their mutation profile using the Sequenom OncoCarta Panel v1.0 and Sanger sequencing for PTEN, PIK3CA, and PIK3R1 transcripts, and their protein and phospho-protein expression levels of PI3K and MAPK signaling pathway components. The cell line panel was treated with pan-class I PI3K, p110α and p110β isoform-specific, allosteric mTOR, mTOR kinase, dual PI3K/mTOR, MEK and RAF inhibitors, and the correlations between protein expression, gene mutations, and sensitivity to targeted therapeutics determined. RNA interference was employed to assess effects of KRAS silencing on EEC cells. Results: The prevalence of PI3K pathway mutations in the EEC cell line panel studied mirrored that reported for primary EECs. PI3K pathway activation as determined by levels of AKTSer473 phosphorylation was significantly associated with PTEN but not PIK3CA or KRAS mutation status. EEC cell lines harboring PIK3CA and PTEN mutations were selectively sensitive to the pan-class I PI3K inhibitor GDC-0941 and allosteric mTOR inhibitor Temsirolimus, respectively. Subsets of EEC cells with concurrent PIK3CA and/or PTEN and KRAS mutations were sensitive to PI3K pathway inhibition. Only 2/6 KRAS-mutant EEC cell lines showed response to MEK inhibition, and KRAS siRNA silencing did not induce apoptosis in KRAS-mutant EEC cells. EEC cell lines harboring PTEN mutations were resistant to the p110β inhibitors GSK2636771 and AZD6482, and only combination with the p110α selective inhibitor A66 resulted in a decrease in cell viability. Conclusions: Our findings provide evidence to suggest that selective pan-PI3K and mTOR inhibition in EEC cells may be most effective in PIK3CA- and PTEN-mutant cancers, respectively, and that these PI3K inhibitors may even be effective in a subset of EECs concurrently harboring KRAS mutations. Our results further demonstrate that p110β inhibition alone is not sufficient to sensitize PTEN-mutant EEC cells, suggesting that combination with other targeted agents may be required to increase efficacy. Citation Format: Britta Weigelt, Patricia H. Warne, Maryou B. Lambros, Jorge S. Reis-Filho, Julian Downward. PI3K pathway dependencies in endometrioid endometrial cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4472. doi:10.1158/1538-7445.AM2013-4472