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

## TL;DR

This study explores how different TP53 R175 mutations in ovarian cancer affect drug resistance and tumor progression, revealing distinct molecular mechanisms and potential treatment strategies.

## Contribution

The study identifies distinct functional roles of TP53 R175 mutations and their associated molecular pathways in platinum-resistant ovarian cancer.

## Key findings

- p53R175G and p53R175H mutations confer resistance to different agents and promote tumor progression via distinct regulatory networks.
- CHD1 selectively interacts with p53R175G to regulate its transcriptional activity, including IL7R target genes.
- CHD1 knockdown or IL7R inhibition synergistically enhances platinum sensitivity in R175G-mutated tumors.

## Abstract

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 p53R175H and p53R175G mutations at Arg175 revealed distinct roles in tumor cell migration and drug resistance, with p53R175G conferring resistance to agents targeting p53R175H. Through multi-omics sequencing analysis, it was discerned that p53R175H and p53R175G promoted tumor progression through distinct cofactors and regulatory networks. p53R175H mediated upregulation of extracellular matrix-related genes, whereas p53R175G activated pathways associated with cytokine receptor interaction and membrane trafficking. Notably, the chromatin remodeling protein CHD1 selectively interacted with p53R175G, but not p53R175H, and regulated the transcriptional activity of p53R175G, 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.