Abstract 3479: Sensitivity of endometrial cancer cells to inhibitors targeting different nodes of the PI3K pathway and their combination with a MEK inhibitor.
Authors: Wongchenko Matthew J. , Guan Yinghui , Wagle Marie-Claire , Ryner Lisa , Lu Shan , Koeppen Hartmut , Hampton Garret , Lackner Mark , Wang Yulei , Yan Yibing 
Published: August 2014

Activation of the PI3K pathway has been reported in endometrial cancers, and there are a number of inhibitors targeting different nodes of the PI3K pathway currently in clinical trials, including the PI3K/mTOR dual inhibitor GDC-0980 that is in a phase II trial for endometrial cancer (NCT01455493). In this study, we set to examine the prevalence of overlapping mutational activation of the PI3K pathway with other pathways, such as MAPK. We also tested whether targeting different nodes of PI3K pathway, such as PI3K, AKT, or PI3K/mTOR could exert differential effects on endometrial cancer cells, and whether combination with a MEK inhibitor could provide an additional benefit in inhibiting endometrial cancer cell growth.

Alteration of oncogenes and tumor suppressor genes were profiled in 80 endometrial cancer samples by qRT-PCR, targeted deep sequencing, and IHC staining. Multiple PI3K inhibitors, including GDC-0941 (PI3K), GDC-0068 (AKT), GDC-0980 (PI3K/mTOR), and the MEK inhibitor GDC-0973 were tested in a panel of 27 endometrial cancer cell lines for their effects on cell growth. Cell signaling status at baseline and on-treatment was profiled by reverse phase protein array. Mutations and copy number variations of relevant oncogenes and tumor suppressor genes were examined in these cells by targeted deep sequencing.

In the 80 endometrial tumor tissues we profiled, there were multiple instances of PI3K pathway alteration including 31% PIK3CA mutations, 9% AKT1 mutations, 16% MET mutations, and 38% PTEN null. In addition, KRAS mutations significantly overlapped with PTEN null or PIK3CA mutation in the same specimen. Endometrial cancer cell lines had distinct patterns of sensitivity to inhibitors targeting different nodes of the PI3K pathway. Preliminary results showed that GDC-0068 was more effective in cell lines with PTEN mutations, while GDC-0941 had a greater effect on those with PIK3CA mutations, and the cell lines were broadly sensitive to GDC-0980. In spite of the widespread activation of the PI3K pathway in endometrial cancer cells, synergistic inhibition of cell growth was observed when GDC-0973 was combined with either GDC-0068 or GDC-0941 in most of the cell lines tested. We will seek to identify genomic and/or proteomic features that will allow better selection as to which node of the PI3K pathway to target, and when to combine with a MEK inhibitor.

Citation Format: Matthew J. Wongchenko, Yinghui Guan, Marie-Claire Wagle, Lisa Ryner, Shan Lu, Hartmut Koeppen, Garret Hampton, Mark Lackner, Yulei Wang, Yibing Yan. Sensitivity of endometrial cancer cells to inhibitors targeting different nodes of the PI3K pathway and their combination with a MEK inhibitor. [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 3479. doi:10.1158/1538-7445.AM2013-3479