Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China.
National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China.
Nat Commun. 2023 Nov 16;14(1):7430. doi: 10.1038/s41467-023-42850-x.
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）在同源重组（HR）缺陷（HRD）的卵巢癌（OC）中具有选择性活性，这种 HRD 是由 BRCA1/2 和其他 DNA 修复途径成员的突变引起的。我们寻求诱导 HR 功能正常的细胞中出现 HRD 的分子靶向治疗方法，以与 PARPi 诱导合成致死，并扩展 PARPi 的应用。在这里，我们证明赖氨酸特异性去甲基酶 1（LSD1）是 OC 的一个重要调节因子。重要的是，LSD1 的遗传缺失或药理学抑制会诱导 HRD，并使 HR 功能正常的 OC 细胞对 PARPi 在体外和多种体内模型中敏感。从机制上讲，LSD1 的抑制作用直接损害了 BRCA1/2 和 RAD51 的转录，这三个基因对 HR 至关重要，且不依赖于其典型的去甲基酶功能。总的来说，我们的工作表明，联合 LSD1 抑制剂可以极大地扩展 PARPi 在 HR 功能正常的肿瘤患者中的应用，值得在人类临床试验中进行评估。
