HER2; p53 Co-mutated Cancers Show Increased Histone Acetylation and are Sensitive to Neratinib plus Trastuzumab Deruxtecan

In metastatic breast cancer, HER2 -activating mutations often co-occur with TP53 mutations, a combination linked to poor response to neratinib and worse prognosis. To model this clinical challenge, we bred HER2 V777L transgenic mice with two TP53 mutant alleles: TP53 R172H (the murine homolog of human TP53 R175H) and TP53 fl/fl , which mimics p53 truncations common in human tumors. TP53 mutations accelerated tumor development and reduced survival in HER2 -mutant mice. These co-mutant tumors were resistant to neratinib but remained sensitive to exatecan, the topoisomerase I (TOP1) inhibitor payload in trastuzumab deruxtecan (T-DXd). Mechanistically, TP53 mutant tumors exhibited upregulation of histone acetylation, hypertranscription of DNA repair factors, increased chromatin accessibility, and rendered cells more susceptible to TOP1 inhibitors via G2/M arrest and apoptosis. This vulnerability is dependent on transcriptional activity of TP53 mutations, highlighting a novel strategy to treat HER2;TP53 co-mutant breast cancers using TOP1-targeted therapies. Statement of Significance TP53 mutations sensitize HER2-mutant cancers to TOP1 inhibitors via chromatin accessibility and hyper-transcription, supporting combination therapy with neratinib and T-DXd in TP53 /HER2 co-mutant breast cancers.