Fernandez Anell, Artola Maider, Leon Sergio, Otegui Nerea, Jimeno Aroa, Serrano Diego, Calvo Alfonso
Program in Solid Tumors, CIMA, Cancer Center Clinica Universidad de Navarra (CCUN), University of Navarra, Avenida de Pio XII, 55, 31008 Pamplona, Spain.
Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain.
Cells. 2025 May 20;14(10):748. doi: 10.3390/cells14100748.
Eliciting DNA damage in tumor cells continues to be one of the most successful strategies against cancer. This is the case for classical chemotherapy drugs and radiotherapy. In the modern era of personalized medicine, this strategy tries to identify specific vulnerabilities found in each patient's tumor, to inflict DNA damage in certain cell contexts that end up in massive cancer cell death. Cells rely on multiple DNA repair pathways to fix DNA damage, but cancer cells frequently exhibit defects in these pathways, many times being tolerant to the damage. Key vulnerabilities, such as mutations, have been exploited with PARP inhibitors, leveraging synthetic lethality to selectively kill tumor cells and improving patients' survival. In the DNA damage response (DDR) network, kinases ATM, ATR, Chk1, and Chk2 coordinate DNA repair, cell cycle arrest, and apoptosis. Inhibiting these proteins enhances tumor sensitivity to DNA-damaging therapies, especially in DDR-deficient cancers. Several small-molecule inhibitors targeting ATM/Chk2 or ATR/Chk1 are currently being tested in preclinical and/or clinical settings, showing promise in cancer models and patients. Additionally, pharmacological blockade of ATM/Chk2 and ATR/Chk1 axes enhances the effects of immunotherapy by increasing tumor immunogenicity, promoting T-cell infiltration and activating immune responses. Combining ATM/Chk2- or ATR/Chk1-targeting drugs with conventional chemotherapy, radiotherapy or immune checkpoint inhibitors offers a compelling strategy to improve treatment efficacy, overcome resistance, and enhance patients' survival in modern oncology.
引发肿瘤细胞中的DNA损伤仍然是对抗癌症最成功的策略之一。传统化疗药物和放射疗法就是如此。在个性化医疗的现代时代，这一策略试图识别每个患者肿瘤中发现的特定脆弱性，在某些细胞环境中造成DNA损伤，最终导致大量癌细胞死亡。细胞依靠多种DNA修复途径来修复DNA损伤，但癌细胞在这些途径中经常表现出缺陷，很多时候对损伤具有耐受性。关键的脆弱性，如突变，已被PARP抑制剂利用，利用合成致死性来选择性杀死肿瘤细胞并提高患者的生存率。在DNA损伤反应（DDR）网络中，激酶ATM、ATR、Chk1和Chk2协调DNA修复、细胞周期停滞和细胞凋亡。抑制这些蛋白质可增强肿瘤对DNA损伤疗法的敏感性，尤其是在DDR缺陷型癌症中。目前有几种靶向ATM/Chk2或ATR/Chk1的小分子抑制剂正在临床前和/或临床环境中进行测试，在癌症模型和患者中显示出前景。此外，对ATM/Chk2和ATR/Chk1轴的药物阻断通过增加肿瘤免疫原性、促进T细胞浸润和激活免疫反应来增强免疫疗法的效果。将靶向ATM/Chk2或ATR/Chk1的药物与传统化疗、放疗或免疫检查点抑制剂联合使用，为提高现代肿瘤学的治疗效果、克服耐药性和提高患者生存率提供了一个引人注目的策略。
