The G2 checkpoint inhibitor CBP-93872 increases the sensitivity of colorectal and pancreatic cancer cells to chemotherapy

CBP-93872 suppresses maintenance of DNA double-stranded break-induced G2 checkpoint, by inhibiting the pathway between ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) activation. To examine the potential use of CBP-93872 for clinical applications, we analyzed the synergistic effects of platinum-containing drugs, oxaliplatin and cisplatin, pyrimidine antimetabolites, gemcitabine and 5-fluorouracil (5-FU), in combination with CBP-93872, on cell lethality in colorectal and pancreatic cancer cell lines. Treatment with CBP-93872 significantly increased cancer cell sensitivities to various chemotherapeutic agents tested through suppression of checkpoint activation. Our results thus reveal that combination treatment of CBP-93872 with known chemotherapeutic agents inhibits phosphorylation of ATR and Chk1, and induces cell death.

CBP-93872可通过抑制共济失调毛细血管扩张症突变激酶（ataxia-telangiectasia mutated, ATM）与ATM及Rad3相关激酶（ATM- and Rad3-related, ATR）的激活通路，阻断DNA双链断裂诱导的G2检查点的维持。为探究CBP-93872的临床应用潜力，本研究分析了CBP-93872与铂类药物（奥沙利铂、顺铂）、嘧啶类抗代谢药物（吉西他滨与5-氟尿嘧啶，5-FU）联合使用时，对结直肠癌及胰腺癌细胞系的细胞致死性协同效应。经CBP-93872处理后，癌细胞对本次实验所测试的各类化疗药物的敏感性显著提升，该效应通过抑制检查点激活实现。本研究结果显示，CBP-93872与现有化疗药物联合给药可抑制ATR及检查点激酶1（Chk1）的磷酸化，并诱导细胞死亡。