Maureen E. Murphy

Mutant p53 binds and controls estrogen receptor activity to drive endocrine resistance in ovarian cancer

High-grade serous ovarian cancer (HGSOC) is a highly lethal gynecologic malignancy in women. Women diagnosed with HGSOC initially respond to chemotherapy, but there is a >80% rate of relapse. There is thus a significant unmet need for new therapeutic targets for HGSOC. Estrogen receptor α (ERα) is a particularly attractive candidate, as ∼70% of HGSOC tumors stain positively for ERα and there are approved inhibitors that show limited toxicity. However, unlike the case for breast cancer, endocrine therapy for HGSOC has not shown consistently promising results. In this work, we show that missense mutant forms of p53, which occur in >60% of HGSOC, bind and inhibit ERα function and confer resistance to fulvestrant and elacestrant. Mechanistically, we show that mutant p53 predominantly inhibits one arm of the ERα pathway—the transactivation of jointly regulated ERα–SP1 target genes such as the mTOR regulator DEPTOR . We show that silencing mutant p53 restores the ability of ERα to transactivate ERα–SP1 target genes and renders HGSOC markedly more sensitive to endocrine therapy. Consistent with this premise, we show that the p53 mutant Y220C refolding compound rezatapopt enhances fulvestrant response in a Y220C mutant cell line.