Cancer Therapy: Preclinical PI3K Pathway Dependencies in Endometrioid Endometrial Cancer Cell Lines

Purpose: Endometrioid endometrial cancers (EEC) frequently harbor coexisting mutations in phosphoinositide 3-kinase (PI3K) pathway genes, including PTEN, PIK3CA, PIK3R1, and KRAS. We sought to define the genetic determinants of PI3K pathway inhibitor response in EEC cells, andwhether PTEN-mutant EEC cell lines rely on p110b signaling for survival. Experimental Design: Twenty-four human EEC cell lines were characterized for their mutation profile and activation state of PI3K andmitogen-activated protein kinase (MAPK) signaling pathway proteins. Cells were treatedwith pan-class I PI3K, p110a, and p110b isoform-specific, allostericmTOR,mTORkinase, dual PI3K/mTOR, mitogen-activated protein/extracellular signal–regulated kinase (MEK), and RAF inhibitors. RNA interference (RNAi) was used to assess effects of KRAS silencing in EEC cells. Results: EEC cell lines harboring PIK3CA and PTENmutations 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, and only 2 of 6 KRAS-mutant cell lines showed response to MEK inhibition. KRAS RNAi silencing did not induce apoptosis in KRAS-mutant EEC cells. PTEN-mutant EEC cell lines were resistant to the p110b inhibitorsGSK2636771 andAZD6482, andonly in combinationwith thep110a selective inhibitor A66was a decrease in cell viability observed. Conclusions:Targetedpan-PI3K andmTOR inhibition inEEC cellsmaybemost effective inPIK3CAand PTEN-mutant tumors, respectively, even in a subset of EECs concurrently harboring KRAS mutations. Inhibition of p110b alone may not be sufficient to sensitize PTEN-mutant EEC cells and combination with other targeted agents may be required. Clin Cancer Res; 19(13); 3533–44. 2013 AACR.