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

In metastatic breast cancer, -activating mutations often co-occur with mutations, a combination linked to poor response to neratinib and worse prognosis. To model this clinical challenge, we bred transgenic mice with two mutant alleles: (the murine homolog of human R175H) and , which mimics p53 truncations common in human tumors. mutations accelerated tumor development and reduced survival in -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, 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 mutations, highlighting a novel strategy to treat co-mutant breast cancers using TOP1-targeted therapies.