MGMT甲基化MSS型转移性结直肠癌患者TMZ和ICIs联合治疗  

Combined Therapy of TMZ and ICIs in MSS mCRC Patients with MGMT Methylation

作　　者：牛静秀[1] 张利红[1] 王辉[1] 王华庆[1] NIU Jingxiu;ZHANG Lihong;WANG Hui;WANG Huaqing(Tianjin Union Medical Center,Department of Oncology,Institute of Integrative Oncology,Tianjin 300121,China)

机构地区：[1]天津市人民医院肿瘤诊疗中心,天津300121

出　　处：《标记免疫分析与临床》2024年第12期2354-2357,共4页Labeled Immunoassays and Clinical Medicine

基　　金：天津市自然科学基金多元投入基金(编号:21JCYBJC01830);天津市医学重点学科(专科)建设项目资助(编号:TJYXZDXK-053B)。

摘　　要：一部分转移性结直肠癌(metastatic colorectal cancer,mCRC)患者经历了前线系统治疗后出现了继发耐药,还有一部分患者对所有批准的抗肿瘤药物原发耐药,但这些患者中的一部分人的体能状态仍能耐受进一步的抗肿瘤治疗,这对后续治疗的选择提出了挑战。O6-甲基鸟嘌呤DNA甲基转移酶(methylguanine DNA methyltransferase,MGMT)甲基化导致的MGMT水平的降低为烷化剂替莫唑胺(temozolomide,TMZ)的有效性提供了可能,大约30%~40%的mCRC会发生MGMT基因启动子甲基化。在没有MGMT表达的情况下,机体对替莫唑胺产生的碱基错配会调用错配修复途径进行修复,但修复在没有MGMT的情况下最终导致细胞停滞和死亡。MGMT甲基化的微卫星稳定(microsatellite-stable,MSS)mCRC对TMZ有效的可能性增加。在mCRC中,免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)对占mCRC的95%的MSS型疗效较差。在MSS mCRC患者中探索联合使用TMZ和ICIs的基本原理是通过TMZ激活有效的免疫监视,相关的基础和临床研究正在进行。A part of metastatic colorectal cancer(mCRC) patients who heve received frontline system treatments appeared secondary resistance,and some patients showed resistant to anti-tumor drugs at the very start,namely primary resistance,but some of these patients can tolerate further anti-tumor treatment.How to make a choice of subsequent treatment for these patients is a big challenge.The reduction of MGMT levels caused by methylation of O6-methylguanine DNA methyltransferase( MGMT) offers the possibility of the effectiveness of temozolomide,occurring in approximately 30%-40% of MGMT gene promoter methylation in mCRC.In the absence of MGMT expression,mismatch repair(MMR) proteins repair cellular damage caused by alkylating agents,but the repairment eventually leads to cell arrest and death in the absence of MGMT.MGMT methylation of the microsatellite-stable(MSS)mCRC is more likely to be effective in response to TMZ.In mCRC,immune checkpoint inhibitors(ICIs) are less effective to the patients who are MSS types,which account for 95% of mCRC.The rationale for exploring the combined use of TMZ and ICIs in MSS mCRC patients is effective immune surveillance through TMZ activation,and relevant basic and clinical studies are ongoing.

关 键 词：甲基鸟嘌呤DNA甲基转移酶 转移性结直肠癌 替莫唑胺 免疫检查点抑制剂 微卫星稳定 

分 类 号：Q523[生物学—生物化学]