精准医学的新策略--“协同致死”机制及其在胰腺癌中的应用

A new strategy of precision medicine-“Synthetic lethality”principle in pancreatic cancer

预计到2030年,胰腺癌将成为全球第2位的致死性肿瘤,随着人口的老龄化,我国的胰腺癌发病率也呈快速增长趋势。胰腺癌被诊断时80%~85%的患者已不能切除或已经转移,其5年生存率低于10%。近年来,尽管发展了一些针对胰腺癌新的治疗策略,但取得的效果非常有限,其治疗仍是一个挑战性的问题。“协同致死”是一个新的治疗策略,它是基于DNA损伤修复通路的一个通路中关键基因的缺失,而针对性的抑制其补偿通路,造成肿瘤细胞的DNA损伤无法修复进入有丝分裂期,通过有丝分裂灾难机制而导致细胞的死亡。DNA损伤修复基因(如BRCA1/2)在胰腺癌中的突变率较低,而且表观遗传异常改变更常见。另外,其他信号通路(如:PI3K、AKT、Wnt、SMAD4)的异常改变也会直接或间接影响DNA损伤修复。基于“协同致死”原理和“BRCAness”效应探索新的治疗策略,将扩展“协同致死”治疗的应用范围。

Pancreatic cancer is the most deadly cancer with a 5-year survival rate less than 10%.The incidence of pancreatic cancer is increasing fast and it will become the second leading cause of cancer-related death by 2030.Despite advances in surgical approaches,various chemotherapy regimens and immune therapeutics,its poor prognosis has not improved.Numerous researchers are developing new approaches to target oncogenes,while most of the results are unsatisfactory.Synthetic lethality is a novel strategy to kill cancer cell by targeting the compensation pathway of the defected DNA damage repair(DDR)signaling.Promoter region methylation is frequently in DDR and related genes.Epigenetics joins the Knudson’s“two hit”theory.Aberrant epigenetic changes in DDR regulators and related genes may serve as a new avenue for“synthetic lethality”strategy in pancreatic cancer.