p53-PIK3CA in HGSOC. Deciphering Mutant p53-PIK3CA Nexus: Opportunities for Targeted Therapy in High-Grade Serous Ovarian Cancer

High-Grade Serous Ovarian Cancer (HGSOC), the most prevalent ovarian cancer subtype, currently treated with platinum-taxol-based chemotherapy, has a dismal five-year survival rate (>30%). Emergence of platinum resistance and recurrence are major challenges and targeted therapy, such as PARP inhibitors, exhibit efficacy within a limited patient population, warranting the need to identify new therapeutic targets. Herein, we aim to devise novel therapeutic approaches based on the genomic landscape of HGSOC, which predominantly has TP53 mutations and amplifications in the PI3K/AKT pathway. To decode the molecular interplay between mutant-p53 and the oncogenic PI3K/AKT pathway and assess the efficacy of the PIK3CA inhibitor, Alpelisib, we created a small repertoire of oncogenic p53 mutants, identified from TCGA data, in p53-null SKOV3 cells, wherein mutant expressing cells demonstrated varied responses to cisplatin. Notably, R282W and R175H mutants exhibited elevated PIK3CA expression post-Cisplatin treatment, rendering them more susceptible to the combinatorial treatment of Cisplatin-Alpelisib. This treatment regime was further validated in malignant ascites-derived tumour cells obtained from a small cohort of treatment-naïve and relapsed HGSOC patients. Impressively, the Cisplatin-Alpelisib combination induced heightened apoptosis in 33% of samples, most of which harboured PIK3CA gene amplifications (80%). Through next-generation sequencing, a previously unreported TP53 mutation, R196Q, which displayed significant sensitivity to the Cisplatin-Alpelisib treatment, was identified and further validated in SKOV3 cells, where similar results were observed. Chromatin Immunoprecipitation assay revealed a diminished affinity of R196Q mutant to the PIK3CA promoter upon cisplatin treatment, contrasting to wild-type p53, where cisplatin treatment led to enhanced binding and subsequent repression of PIK3CA transcription. This indicates a direct involvement of specific p53 mutants in modulating PIK3CA expression. Thus, our study highlights the efficacy of the Cisplatin-Alpelisib combination in a small subset of HGSOC patients with altered PIK3CA (at chromosomal or transcriptional level), which can be exploited as a new therapeutic approach.