Kciuk Mateusz, Gruszka Renata, Aleksandrowicz Marta, Śliwińska Agnieszka, Kontek Renata
Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland.
Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 A. Pawińskiego Street, 02-106 Warsaw, Poland.
Int J Mol Sci. 2025 Aug 9;26(16):7709. doi: 10.3390/ijms26167709.
Gastric cancer remains a significant global health challenge, with regional and demographic disparities in incidence, mortality, and treatment outcomes. Despite advances in screening and early detection, prognosis remains poor for many patients, particularly those with advanced disease. Recent insights into DNA damage response pathways have uncovered critical molecular vulnerabilities in gastric tumors, including frequent mutations, loss, deficiency, and oncogene-driven replication stress, which render these cancers highly dependent on the ATR-CHK1 axis for survival. This review synthesizes current clinical and preclinical evidence on ATR and CHK1 inhibitors as therapeutic strategies in gastric cancer. Emphasis is placed on synthetic lethality, immune modulation, and the potential for combination regimens with chemotherapy, radiotherapy, or immune checkpoint blockade. Mechanisms of resistance, including transcription-associated replication stress modulation and bypass signaling networks, are discussed, alongside strategies to predict and overcome therapeutic failure. The review also highlights the importance of biomarker-guided patient selection, adaptive dosing to reduce toxicity, and refined pharmacodynamic monitoring to enhance therapeutic precision. Collectively, these insights support the rational integration of ATR-CHK1 inhibitors into clinical protocols for biomarker-defined gastric cancer subsets and underscore their promise.
胃癌仍然是一项重大的全球健康挑战，在发病率、死亡率和治疗结果方面存在地区和人口差异。尽管在筛查和早期检测方面取得了进展，但许多患者的预后仍然很差，尤其是那些患有晚期疾病的患者。最近对DNA损伤反应途径的深入了解揭示了胃肿瘤中的关键分子脆弱性，包括频繁的突变、缺失、缺陷和癌基因驱动的复制应激，这使得这些癌症高度依赖ATR-CHK1轴来生存。本综述综合了目前关于ATR和CHK1抑制剂作为胃癌治疗策略的临床和临床前证据。重点是合成致死性、免疫调节以及与化疗、放疗或免疫检查点阻断联合方案的潜力。讨论了耐药机制，包括转录相关的复制应激调节和旁路信号网络，以及预测和克服治疗失败的策略。该综述还强调了生物标志物指导的患者选择、降低毒性的适应性给药以及改进的药效学监测以提高治疗精准度的重要性。总体而言，这些见解支持将ATR-CHK1抑制剂合理纳入生物标志物定义的胃癌亚组的临床方案，并强调了它们的前景。
