Mechanistic basis and therapeutic strategies for PPP2R1A mutation in gynecological cancer - Project Summary PPP2R1A encodes the -isoform of the scaffolding A subunit of the protein phosphatase 2A (PP2A) enzyme. PPP2R1A is mutated in >1% of cases across diverse human cancer types. Notably, PPP2R1A mutations are often observed in gynecological cancers. For example, PPP2R1A mutation occurs in up to 40% of uterine serous endometrial carcinoma (USC) and ~10% of ovarian clear cell carcinoma (OCCC). There are currently no effective therapeutic strategies based on PPP2R1A mutational status. Our unbiased screen show that PPP2R1A-mutated gynecological cancers are selectively sensitive to the inhibition of KAT6A, a histone lysine acetyltransferase. KAT6A inhibition induces cellular senescence, a state of stable cell growth arrest, in a PPP2R1A mutation dependent manner. Thus, the overall goal of this proposal is to develop urgently needed novel therapeutic approaches for PPP2R1A-mutated gynecological cancers by targeting the epigenetic regulator KAT6A. In addition, our preliminary data from both preclinical studies and a clinical trial show that immune checkpoint blockades (ICBs) are effective in PPP2R1A-mutated OCCCs. Hence, the objectives of this application are to investigate the mechanistic basis by which PPP2R1A mutant renders cancer cells selectively sensitive to KAT6A inhibition and to explore KAT6A inhibitor-based combination therapeutic strategies for PPP2R1A-mutated cancers. Our central hypothesis is that PPP2R1A-mutated gynecological cancers can be treated and ultimately eradicated by targeting KAT6A in combination with ICBs such as anti-PD-L1 or senolytics that selectively induce apoptosis of senescent cells. Accordingly, two specific aims are proposed: Aim 1 is to investigate the mechanism by which PPP2R1A-mutated gynecological cancer cells are selectively sensitive to KAT6A inhibition and Aim 2 will target the KAT6A histone lysine transferase activity for developing novel therapeutic strategies for PPP2R1A mutation. The proposed studies are highly novel because they explore urgently needed novel therapeutic strategies for PPP2R1A-mutated gynecological cancers by targeting KAT6A using clinically applicable inhibitors in combination with FDA approved senolytics such as ABT263 or immune checkpoint blockade such as anti-PD-L1 antibody. Thus, these results have the potential to develop the first effective therapeutic strategies for PPP2R1A-mutated cancers. The research proposed is of high impact because it will lay the critical foundation for ultimately developing urgently needed therapeutic strategies for eradicating PPP2R1A-mutated cancers. Therefore, the current study will not only provide critical mechanistic insights into the role of PPP2R1A mutation in cancer but will also have far-reaching implications for the development of PPP2R1A mutation-based therapeutic strategies. Further, PPP2R1A mutation occurs across many cancer types including major cancer types. The mechanistic insights gained from the proposed studies will also have broad implications.
