Abstract C030: The Wip1 phosphatase activator QGC-8-52 selectively sensitizes p53-deficient cancer cells to chemotherapy

Abstract PP2C serine-threonine phosphatase Wip1 is vital for tissue homeostasis, stress signaling, and the pathogenesis of various diseases, making it a promising target for cancer therapy. Inhibiting Wip1's expression or activity is a novel strategy to prevent cancer. However, traditional Wip1 suppression may not work in cancers lacking p53. Here, we evaluated a new Wip1 activator, QGC-8-52, in preclinical breast cancer models. QGC-8-52 sensitizes p53-deficient cancer cells to chemotherapy by facilitating Wip1-FOXO3a interaction and dephosphorylation of Thr487, which enhances FOXO3a's activity on the proapoptotic TRAIL gene. This effect is specific to p53-deficient cancer cells. In normal cells, Wip1 activation reduces drug-induced apoptosis by weakening upstream signaling to p53. Thus, activating Wip1 during chemotherapy boosts apoptosis in p53-negative tumors and protects normal tissues. Our findings highlight Wip1 activation as a potentially effective and safe treatment for p53-deficient cancers. Citation Format: Ke Wu, Yong Wu, Jay Vadgama, Qiao-Hong Chen, Zhi-min Huang, Qun Li. The Wip1 phosphatase activator QGC-8-52 selectively sensitizes p53-deficient cancer cells to chemotherapy [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C030.