Repression of PRMT activities sensitize homologous recombination-proficient ovarian and breast cancer cells to PARP inhibitor treatment

An "induced PARP inhibitor (PARPi) sensitivity by epigenetic modulation" strategy is being evaluated in the clinic to sensitize homologous recombination (HR) proficient tumors to PARPi treatments. To expand its clinical applications and identify more efficient combination, we perform a drug screen by combining PARPi with 74 well-characterized epigenetic modulators that target five major classes of epigenetic enzymes. Both type I PRMT inhibitor and PRMT5 inhibitor exhibit high combination and clinical priority scores in our screen. PRMT inhibition significantly enhances PARPi treatment-induced DNA damage in HR-proficient ovarian and breast cancer cells. Mechanistically, PRMTs maintain the expression of genes associated with DNA damage repair and BRCAness, and regulate intrinsic innate immune pathways in cancer cells. Analyzing large-scale genomic and functional profiles from TCGA and DepMap further confirms that PRMT1, PRMT4, and PRMT5 are potential therapeutic targets in oncology. Finally, PRMT1 and PRMT5 inhibitions act synergistically to enhance PARPi sensitivity. Our studies provide a strong rationale for clinical application of a combination of PRMT and PARP inhibitors in the patients with HR-proficient ovarian or breast cancer.

一项旨在使同源重组（HR）功能正常型肿瘤对PARPi治疗增敏的「通过表观遗传调控诱导聚腺苷二磷酸核糖聚合酶抑制剂（PARP inhibitor，PARPi）敏感性」策略目前正于临床中开展评估。为拓展该策略的临床应用范围并筛选更高效的联合治疗方案，我们开展了一项药物筛选实验：将PARPi与74种经过充分表征的、靶向五大类主要表观遗传酶的表观遗传调控剂进行联合给药。在本次筛选中，I型PRMT抑制剂与PRMT5抑制剂均展现出较高的联合用药评分与临床优先级评分。PRMT抑制可显著增强PARPi治疗在HR功能正常型卵巢癌与乳腺癌细胞中诱导的DNA损伤效应。从机制层面而言，PRMT可维持与DNA损伤修复及BRCAness相关基因的表达水平，并调控癌细胞内的固有天然免疫通路。通过分析癌症基因组图谱（The Cancer Genome Atlas，TCGA）与DepMap数据库中的大规模基因组及功能组学特征，进一步证实PRMT1、PRMT4与PRMT5是肿瘤学领域潜在的治疗靶点。最终研究发现，PRMT1与PRMT5抑制剂的联合给药可产生协同效应，进一步增强PARPi敏感性。本研究为PRMT与PARP抑制剂联合疗法在HR功能正常型卵巢癌或乳腺癌患者中的临床应用提供了坚实的理论依据。