Mechanism and targeting strategy of the MYBL2-CLSPN-CHK1 axis driving cisplatin resistance in gastric cancer through regulation of DNA damage repair

Abstract

Cisplatin remains a cornerstone chemotherapeutic agent for advanced gastric cancer; however, the development of drug resistance substantially limits its clinical benefit and is frequently associated with poor prognosis. Recent studies suggest functional interactions between MYBL2 , CLSPN and CHK1 genes and multiple DNA repair pathways, indicating that they may contribute to tumor cell tolerance of cisplatin-induced genotoxic stress. MYBL2 has been implicated in transcriptional regulation of cell cycle and DNA repair–associated genes, CLSPN functions as a mediator of ATR -dependent checkpoint activation, and CHK1 coordinates cell cycle arrest and repair signaling under replication stress conditions. This review aims to examine emerging evidence regarding the roles of MYBL2 , CLSPN and CHK1 in cisplatin resistance in gastric cancer, with particular emphasis on their potential involvement in DNA damage response and replication stress pathways. We further outline a working model in which enhanced proliferative drive and replication stress may increase reliance on checkpoint-mediated repair mechanisms during cisplatin exposure. It should be noted that much of the available evidence is derived from in vitro models or extrapolated from other tumor types, and direct in vivo and clinical validation in gastric cancer remains limited. These findings suggest a regulatory network that may drive cisplatin resistance and reveal potential therapeutic vulnerabilities. Clarifying the context-dependent contribution of this network may ultimately inform biomarker-guided strategies and combination approaches for improving treatment response in gastric cancer.