靶向同源重组修复的抗肿瘤研究进展

Research progress in targeting homologous recombination repair for tumor therapy

聚ADP-核糖聚合酶[poly(ADP-ribose)polymerase,PARP]抑制剂用于治疗同源重组修复缺陷(homologous recombination deficiency,HRDness)的肿瘤类型已成为靶向治疗领域的重大成果之一,但仍然存在大量肿瘤患者缺乏特定的突变基因或出现回复突变而无法受益于PARP抑制剂的单药治疗。利用分子靶向药物造成"chemical HRDness"概念的提出,使靶向同源重组修复成为新的抗肿瘤研究热点。同源重组修复以姐妹染色单体为模板高保真地修复DNA双链断裂,是一个受到严格调控的过程。除了直接抑制同源重组修复通路的关键组分,靶向其调节通路也可造成"HRDness"表型,如靶向细胞周期与检查点调控通路、磷脂酰肌醇-3激酶(phosphatidylinositol3-kinase,PI3K)信号转导通路、表观遗传与染色质重塑通路等。靶向同源重组修复既可与PARP抑制剂联用造成"合成致死",也可与传统的放化疗和新兴的免疫疗法发挥协同抗肿瘤作用。本文将介绍同源重组修复通路与其调节通路,总结靶向同源重组修复的临床前和临床研究进展,梳理该领域目前亟待解决的问题,并对其在抗肿瘤治疗中的应用前景进行展望。

Applying poly(ADP-ribose)polymerase inhibitors(PARPi)to the treatment of cancers with homologous recombination deficiency(HRDness)has been a great advance in the field of molecular therapeutics.However,in the clinic patients lacking the specific mutations or developing reverse mutations in the process of PARPi treatment may not benefit from PARPi monotherapy.Therefore,targeting homologous recombination(HR)repair with molecularly targeted agents is becoming an attractive research focus and is raising the concept of"chemical HRDness".HR repair is an evolutionarily conserved and extensively regulated process that employs sister chromatids as the template to repair DNA double-strand breaks with high fidelity.In addition to directly targeting HR components,modulation of regulatory pathways controlling HR repair is effective in achieving the"HRDness"phenotype;this includes modulation of the cell cycle checkpoint regulatory pathway,the phosphatidylinositol 3-kinase(PI3 K)signaling pathway,the chromatin remodeling pathway,etc.Targeting HR repair can not only result in"synthetic lethality"when combined with PARPi,but also sensitizes cancers to traditional radio/chemotherapy and novel immunotherapy.In this review we describe the HR repair pathway and its regulatory pathways,summarize the preclinical and clinical outcomes of targeting HR repair,discuss the remaining problems in this field and provide a prospective on its application in tumor therapy.