Abstract IA13: Targeting PI3K isoforms in cancer: From mouse genetics to human therapy

Abstract

Abstract The signaling axis of the class-I phosphatidylinositol 3-kinase (PI3K) is perhaps most commonly activated in cancer; activation of this pathway occurs via distinct mechanisms that include somatic activating mutations in PIK3CA (the gene encoding the p110α isoform of PI3K), genetic or epigenetic loss of the PTEN tumor suppressor and mutation/overexpression of RTKs. Thus PI3K represents an attractive target for cancer therapy and tremendous efforts are being devoted to developing effective PI3K inhibitors for cancer treatment. There are several PI3K isoforms in mammals, only the p110α and p110β isoforms are ubiquitously expressed. While the majority of the signal downstream of nearly all the RTKs and oncogenes so far tested is carried through p110α, p110β appears to play a prominent role in G protein mediated signaling in cells and for RTK signaling in certain circumstances. Surprisingly, we found that p110β is also the major player in a number of tumors driven by PTEN loss. In the mouse, each enzyme has been found to be necessary for certain processes and dispensable for others. Taking both genetic and pharmacological approaches, we have found that the two isoforms can actually play opposing roles in the normal development and pathology of mammary tissue. More recently, we found that p110α and p110β isoforms play spatially distinct roles in the epidermal skin that are required for the development and maintenance of PTEN hamartoma tumor syndrome. In this talk, I will discuss our most recent results on our studies of the distinct roles of the two isoforms in cancer. Citation Format: Jean J. Zhao. Targeting PI3K isoforms in cancer: From mouse genetics to human therapy. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA13.