Perspectives on targeting the phosphatidylinositol 3-kinase pathway for personalized medicine in endometrial and ovarian cancers

Abstract

Endometrial and ovarian cancers show similar genetic and pathological backgrounds. In particular, high frequencies of activating mutations in the phosphatidylinositol 3-kinase (PI3K) pathway, including mutations in PIK3CA and PTEN, are found in both estrogen-dependent endometrial cancer (type I endometrioid carcinomas) and ovarian clear cell and endometrioid carcinomas. In this review, we focus on the PI3K pathway as a potential molecular target for personalized therapies in endometrial and ovarian cancers. We found that targeting the PI3K/mammalian target of rapamycin (mTOR) pathway produced anti-tumor effects in endometrial cancer upon suppression of the PI3K pathway. The presence of KRAS mutations may be a marker for resistance to the inhibition of the PI3K/mTOR pathway. However, the combination of a PI3K/mTOR pathway inhibitor and a MAPK pathway inhibitor, such as a MEK inhibitor, has been shown to suppress cell proliferation synergistically in certain endometrial cancers. In addition, PI3K/mTOR pathway inhibition sensitized endometrial cancer cells to ionizing radiation and produced anti-tumor effects in ovarian clear cell carcinomas in both in vitro and in vivo studies. Moreover, inhibition reduced the phosphorylation levels of MDM2 (a negative regulator of TP53), stabilized TP53, and induced TP53-mediated apoptosis. The activation of TP53 was associated with increased phosphorylation of TP53 on Ser-46, and its downstream target genes, such as TP53AIP1. These findings demonstrate that targeting of the PI3K pathway in both endometrial and ovarian clear cell carcinomas warrants further investigation, including in clinical trials.