Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib selectively kills cancer cells with BRCA-deficiency and is approved for BRCA-mutated breast, ovarian and pancreatic cancers by FDA. However, phase III study of olaparib failed to show a significant improvement in overall survival in patients with gastric cancer (GC). To discover an effective biomarker for GC patient-selection in olaparib treatment, we analyzed proteomic profiling of 12 GC cell lines. MTA2 was identified to confer sensitivity to olaparib by aggravating olaparib-induced replication stress in cancer cells. Mechanistically, we applied Cleavage Under Targets and Tagmentation assay to find that MTA2 proteins preferentially bind regions of replication origin-associated DNA sequences, which could be enhanced by olaparib treatment. Furthermore, MTA2 was validated here to render cancer cells susceptible to combination of olaparib with ATR inhibitor AZD6738. In general, our study identified MTA2 as a potential biomarker for olaparib sensitivity by aggravating olaparib-induced replication stress.

聚（ADP-核糖）聚合酶（PARP）抑制剂奥拉帕尼选择性杀死 BRCA 缺陷的癌细胞，并被 FDA 批准用于 BRCA 突变的乳腺癌、卵巢癌和胰腺癌。然而，奥拉帕尼的 III 期研究未能显示胃癌 (GC) 患者总生存期的显着改善。为了发现奥拉帕尼治疗中 GC 患者选择的有效生物标志物，我们分析了 12 个 GC 细胞系的蛋白质组学分析。MTA2 被鉴定为通过加重奥拉帕尼诱导的癌细胞复制应激来赋予奥拉帕尼敏感性。从机制上讲，我们应用了靶标下的裂解和标记分析来发现 MTA2 蛋白优先结合复制起点相关 DNA 序列的区域，这可以通过奥拉帕尼处理来增强。此外，MTA2 在这里得到验证，使癌细胞对奥拉帕尼与 ATR 抑制剂 AZD6738 的组合敏感。总的来说，我们的研究通过加重奥拉帕尼诱导的复制压力，将 MTA2 确定为奥拉帕尼敏感性的潜在生物标志物。