DNA abasic sites act as rational therapeutic targets to synergize temozolomide response in both MMR-proficient and deficient cancer

Abstract

Abstract Temozolomide (TMZ) is widely used in cancer treatment, yet resistance to this agent limits its therapeutic effectiveness, particularly in mismatch-repair (MMR) deficient cancer. Concurrently, the Base Excision Repair (BER) pathway exerts a mitigating role. Our results demonstrated that the increasing TMZ concentrations correlate with an elevated accumulation of DNA abasic sites via the BER pathway in both MMR-proficient and deficient cancer cells, implicating abasic sites as promising targets to enhance the TMZ response. Amino-quinoxaline small molecules (RA-1) have been developed, whose hydrophobic core facilitates selective binding to apurinic/apyrimidinic (AP) sites, particularly adenine as the complementary nucleobase opposite to the AP-sites via base stacking. RA-1 effectively cleaves TMZ-induced DNA abasic sites in-vitro at minimal concentrations through Schiff-base formation. Remarkably, the combination of TMZ and RA-1 exerts a notable synergistic effect on both types of cells. The underlying mechanism of this synergy is rooted in the cleavage of TMZ-induced DNA abasic sites, which impairs the BER pathway, leading to the formation of DNA double-strand breaks. Consequently, the ATM-Chk2/ATR-Chk1 signalling pathways are activated, prompting S-phase arrest and ultimately driving apoptosis. These findings provide a compelling rationale for targeting DNA abasic sites to synergistically augment TMZ responses in both MMR-proficient and deficient cancer cells.