Homologous recombination–deficient (HRD) tumours, including those harbouring mutations in the BRCA genes, are hypersensitive to treatment with inhibitors of poly(ADP-ribose) polymerase (PARPis). Despite high response rates, most HRD cancers ultimately develop resistance to PARPi treatment through reversion mutations or genetic/epigenetic alterations to DNA repair pathways. Counteracting these resistance pathways, thereby increasing the potency of PARPi therapy, represents a potential strategy to improve the treatment of HRD cancers. In this review, we discuss recent insights derived from genetic screens that have identified a number of novel genes that can be targeted to improve PARPi treatment of HRD cancers and may provide a means to overcome PARPi resistance.

同源重组缺陷 (HRD) 肿瘤，包括那些携带BRCA基因突变的肿瘤，对聚（ADP-核糖）聚合酶 (PARPis) 抑制剂治疗过敏。尽管缓解率很高，但大多数 HRD 癌症最终会通过回复突变或 DNA 修复途径的遗传/表观遗传改变而对 PARPi 治疗产生耐药性。抵消这些耐药途径，从而提高 PARPi 治疗的效力，是改善 HRD 癌症治疗的潜在策略。在这篇综述中，我们讨论了从基因筛选中得出的最新见解，这些基因筛选已经确定了许多新基因，这些基因可以作为改善 PARPi 对 HRD 癌症的治疗的目标，并可能提供一种克服 PARPi 耐药性的方法。