靶向DNA损伤修复通路的胰腺癌治疗策略

Targeting DNA damage repair pathway for pancreatic cancer therapy

随着新的免疫治疗和靶向治疗的发展,其他肿瘤的预后明显得到改善。但胰腺癌的5年生存率一直维持在10%以下,是极具挑战性的恶性肿瘤,亟待寻找新的治疗策略。DNA损伤修复通路形成复杂的调控网络,其功能缺陷将导致肿瘤的发生,但同时增加对基因毒性药物及放射治疗的敏感性。DNA损伤修复通路的异常与恶性肿瘤的发展和肿瘤的耐药密切相关,而PARP抑制剂在BRCA1/2缺陷肿瘤中的成功应用,极大地促进了针对DNA损伤修复缺陷肿瘤的分子靶向治疗研究。除PARP抑制剂外,针对ATR、CHK1、WEE1、DNA-PK等DNA损伤修复的抑制剂均已进入临床试验。在转移性胰腺导管癌中发现,15%~20%的患者存在DNA损伤修复基因的体细胞突变或种系突变,然而其中的部分突变并不影响基因的功能。DNA损伤修复基因在胰腺癌等肿瘤中频繁发生表观遗传异常改变,深入研究其对DNA修复调控网络的影响,有望获得新的“协同致死”治疗策略。

With the development of immunotherapies and target therapy,the survival time has been extended in other cancers,however,the 5 years overall survival of pancreatic cancer patient remains below 10%.It is still a challenge for treatment pancreatic cancer and novel strategies are necessary to improve the therapeutic efficiency.DNA damage repair(DDR)system was developed to be a complex network by distinct signaling pathways.Defect of DDR pathways will sen-sitize cancer cells to chemo-radiotherapeutics.Targeting DDR pathways in DDR abnormal changed cancer individuals may increase the specificity and reduce toxicity.It will enforce the efficiency of genotoxic reagent and decrease the dose in cancer therapy.The successful example is using single strand break repair inhibitor(PARPi)for BRCA1/2 mutated cancer cells.More DDR inhibitors are exploring in preclinical and clinical trials,including inhibitors of ATR,CHK1,WEE1 and DNA-PK.A number of DDR-related genes were discovered owning driver gene mutations,while not all mu-tants are influencing the function of proteins.The abnormal changes of other modifications may also affect the DDR sig-naling function.Based on aberrant epigenetic induced DDR dysregulation has been developed″synthetic lethality″strategy and the efficiency has been verified by experiment.