Temozolomide is an oral alkylating agent used for treating several cancers including glioblastoma and melanoma. Promising, albeit limited, activity and efficacy of temozolomide have been reported in pretreated patients with metastatic colorectal cancer bearing MGMT promoter methylation. MGMT silencing and proficiency of the mismatch repair system were considered the major predictive biomarkers of sensitivity to temozolomide. Refinement of established biomarkers and integration with those related to alteration in specific DNA-damage response pathways such as base excision repair are promising strategies for selecting metastatic colorectal patients to this old drug with several potential novel applications. Then, mounting preclinical and clinical observations have linked acquired resistance to temozolomide to emergence of alterations in the mismatch repair system. Whilst accounting for tumor cells capability of escaping apoptosis when exposed to temozolomide, inactivation of key mismatch-repair proteins will ultimately lead to increasing tumor mutational burden. This drug-induced mismatch deficient-like phenotype is being exploited in proof-of-concept trials combining temozolomide and immune checkpoint inhibitors in metastatic colorectal cancer.

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生物标志物指导的旧药物替莫唑胺的实施作为转移性结直肠癌患者的新型治疗选择。

替莫唑胺是一种口服烷基化剂，用于治疗包括胶质母细胞瘤和黑素瘤在内的多种癌症。据报道，在接受过转移性结直肠癌治疗且携带MGMT启动子甲基化的预治疗患者中，替莫唑胺的活性和疗效有希望，尽管存在局限性。MGMT沉默和错配修复系统的熟练程度被认为是对替莫唑胺敏感的主要预测生物标志物。完善已建立的生物标志物并与那些与特定DNA损伤反应途径的改变（例如碱基切除修复）改变相关的标志物整合，是选择转移性结直肠癌患者使用这种具有多种潜在新用途的旧药物的有前途的策略。然后，越来越多的临床前和临床观察已将对替莫唑胺的获得性耐药与错配修复系统出现的变化联系起来。尽管考虑到暴露于替莫唑胺时肿瘤细胞逃避凋亡的能力，关键失配修复蛋白的失活最终将导致肿瘤突变负担的增加。这种药物诱导的失配缺陷样表型正在转移性结直肠癌联合替莫唑胺和免疫检查点抑制剂的概念验证试验中得到开发。