Distinct functional heterogeneity of TP53 R175 mutations in platinum-resistant ovarian cancer: unveiling molecular mechanisms and therapeutic targets

Ovarian Cancer (OC) is a highly aggressive malignancy in women, and platinum resistance remains a major clinical obstacle. p53 mutations are prevalent in OC and exhibit functional heterogeneity that is associated with therapeutic response and disease progression. However, the roles and mechanisms underlying the functional heterogeneity of p53 mutations in platinum-resistant OC remain elusive. This investigation delineated that p53 mutations within the Loop 2, Loop 3, and β-strand S10 regions were closely linked to platinum resistance. In particular, functional assays unveiled that p53^R175H and p53^R175G mutations at Arg175 revealed distinct roles in tumor cell migration and drug resistance, with p53^R175G conferring resistance to agents targeting p53^R175H. Through multi-omics Sequencing analysis, it was discerned that p53^R175H and p53^R175G promoted tumor progression through distinct cofactors and regulatory networks. p53^R175H mediated upregulation of extracellular matrix-related genes, whereas p53^R175G activated pathways associated with cytokine receptor interaction and membrane trafficking. Notably, the chromatin remodeling protein CHD1 selectively interacted with p53^R175G, but not p53^R175H, and regulated the transcriptional activity of p53^R175G, including target genes such as IL7R. Moreover, CHD1 knockdown or pharmacological inhibition of IL7R synergistically enhanced platinum sensitivity, suggesting promising combination therapies specifically targeting the R175G mutation. The findings revealed that p53 mutations at the same residue exhibited distinct functional properties and relied on unique cofactors, offering valuable insights for precision therapy in OC.