Poly (ADP-ribose) polymerase inhibitors (PARPi) are selectively active in ovarian cancer (OC) with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1/2 and other DNA repair pathway members. We sought molecular targeted therapy that induce HRD in HR-proficient cells to induce synthetic lethality with PARPi and extend the utility of PARPi. Here, we demonstrate that lysine-specific demethylase 1 (LSD1) is an important regulator for OC. Importantly, genetic depletion or pharmacological inhibition of LSD1 induces HRD and sensitizes HR-proficient OC cells to PARPi in vitro and in multiple in vivo models. Mechanistically, LSD1 inhibition directly impairs transcription of BRCA1/2 and RAD51, three genes essential for HR, dependently of its canonical demethylase function. Collectively, our work indicates combination with LSD1 inhibitor could greatly expand the utility of PARPi to patients with HR-proficient tumor, warranting assessment in human clinical trials.

聚 (ADP-核糖) 聚合酶抑制剂 (PARPi) 对由 BRCA1/2 和其他 DNA 修复途径成员突变引起的同源重组 (HR) 缺陷 (HRD) 卵巢癌 (OC) 具有选择性活性。我们寻求分子靶向治疗，在 HR 熟练细胞中诱导 HRD，从而诱导 PARPi 的合成致死并扩展 PARPi 的效用。在这里，我们证明赖氨酸特异性去甲基酶 1 (LSD1) 是 OC 的重要调节因子。重要的是，在体外和多种体内模型中，LSD1 的基因缺失或药理学抑制可诱导 HRD 并使熟练 HR 的 OC 细胞对 PARPi 敏感。从机制上讲，LSD1 抑制直接损害 BRCA1/2 和 RAD51（HR 必需的三个基因）的转录，依赖于其典型的去甲基化酶功能。总的来说，我们的工作表明，与 LSD1 抑制剂联合使用可以极大地扩展 PARPi 对 HR 熟练肿瘤患者的效用，值得在人体临床试验中进行评估。