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

ABSTRACT: 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 o

SUBMITTER: Cheng X 

PROVIDER: S-EPMC12265670 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature