Jan : PI3K isoforms in signaling and cancer; Translating insights from mouse genetics into human therapys

Speaker：Jean J. Zhao, Department of Chemical Biology and Molecular

Host: Prof. Mingyao Liu

When: 2013-1-8  14:00

Where: Conference Room 534, School of Life Sciences

Abstract: The class-I phosphatidylinositol 3-kinase (PI3K) signaling axis is perhaps the most commonly activated signaling pathway 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; however, only the p110 and p110 isoforms are expressed in tumors of epithelial origin. In the mouse, each enzyme has been found to be necessary for certain processes and dispensable for others.  Since it appears likely that inhibitors targeting individual isoforms will prove superior to so called pan inhibitors that were first introduced into the clinic, it has become critical to determine which isoform is important in a given tumor type.  My lab is tackling this problem using both genetic and pharmacological approaches.  I will discuss recent results.  For instance 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 p110 and p110 isoforms play spatially distinct roles in the epidermal skin that are required for the development and maintenance of PTEN hamartoma tumor syndrome. In addition, we are utilizing mouse genetics to focus on the mechanisms by which tumors become resistant to PI3K inhibition.  I will discuss a genetic model of oncogenic PIK3CA-driven tumors that frequently become independent of the initiating oncogene and resistant to PI3K inhibition. Genomic and functional analyses of resistant tumors revealed multiple lesions, providing potential resistance mechanisms to PI3K-targeted therapy.