Mechanistic study of N-acetyltransferase 10 deficiency enhancing olaparib sensitivity in triple negative breast cancer by inhibiting RAD51 N4-acetylcytidine modification.

The treatment of triple-negative breast cancer (TNBC) is challenging due to the lack of common treatment targets, making standard hormonal and targeted therapies ineffective. While PARP inhibitors are promising for TNBC, they are only effective in homologous recombination (HR)-deficient cells with BRCA1/2 mutations. Nevertheless, resistance to PARP inhibitors often develops. Thus, it is imperative to identify strategies or targets that can enhance the efficacy of PARP inhibitors. In this study, we demonstrated that TNBC cells lacking N-acetyltransferase 10 (NAT10) exhibited greater sensitivity to olaparib and extensive DNA double-strand breaks (DSBs). Mechanistically, NAT10 upregulates the N4-acetylcytidine (ac4C) modification of RAD51 mRNA, enhancing its stability and increasing RAD51 expression. Remarkably, the combination of olaparib and remodelin, an inhibitor of NAT10, induced robust anti-tumor effects in vitro and in vivo by promoting DSBs. Our findings illuminate a potential therapeutic strategy targeting NAT10 to enhance olaparib efficacy in TNBC.