Lavudi Kousalya, Banerjee Ananya, Li Na, Yang Yajing, Cai Shurui, Bai Xuetao, Zhang Xiaoli, Li Aidan, Wani Elsa, Yang Shyh-Ming, Zhang Junran, Rai Ganesha, Backes Floor, Patnaik Srinivas, Guo Peixuan, Wang Qi-En
Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
NPJ Precis Oncol. 2023 Jul 10;7(1):66. doi: 10.1038/s41698-023-00411-x.
Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPi) have been approved for both frontline and recurrent setting in ovarian cancer with homologous recombination (HR) repair deficiency. However, more than 40% of BRCA1/2-mutated ovarian cancer lack the initial response to PARPi treatment, and the majority of those that initially respond eventually develop resistance. Our previous study has demonstrated that increased expression of aldehyde dehydrogenase 1A1 (ALDH1A1) contributes to PARPi resistance in BRCA2-mutated ovarian cancer cells by enhancing microhomology-mediated end joining (MMEJ) but the mechanism remains unknown. Here, we find that ALDH1A1 enhances the expression of DNA polymerase θ (Polθ, encoded by the POLQ gene) in ovarian cancer cells. Furthermore, we demonstrate that the retinoic acid (RA) pathway is involved in the transcription activation of the POLQ gene. The RA receptor (RAR) can bind to the retinoic acid response element (RARE) located in the promoter of the POLQ gene, promoting transcription activation-related histone modification in the presence of RA. Given that ALDH1A1 catalyzes the biosynthesis of RA, we conclude that ALDH1A1 promotes POLQ expression via the activation of the RA signaling pathway. Finally, using a clinically-relevant patient-derived organoid (PDO) model, we find that ALDH1A1 inhibition by the pharmacological inhibitor NCT-505 in combination with the PARP inhibitor olaparib synergistically reduce the cell viability of PDOs carrying BRCA1/2 mutation and positive ALDH1A1 expression. In summary, our study elucidates a new mechanism contributing to PARPi resistance in HR-deficient ovarian cancer and shows the therapeutic potential of combining PARPi and ALDH1A1 inhibition in treating these patients.
聚（ADP - 核糖）聚合酶（PARP）抑制剂（PARPi）已被批准用于治疗同源重组（HR）修复缺陷的卵巢癌的一线和复发治疗。然而，超过40%的BRCA1/2突变型卵巢癌对PARPi治疗缺乏初始反应，且大多数初始有反应的患者最终会产生耐药性。我们之前的研究表明，醛脱氢酶1A1（ALDH1A1）表达增加通过增强微同源性介导的末端连接（MMEJ）导致BRCA2突变型卵巢癌细胞对PARPi耐药，但具体机制尚不清楚。在此，我们发现ALDH1A1可增强卵巢癌细胞中DNA聚合酶θ（由POLQ基因编码）的表达。此外，我们证明视黄酸（RA）途径参与了POLQ基因的转录激活。视黄酸受体（RAR）可与位于POLQ基因启动子的视黄酸反应元件（RARE）结合，在RA存在的情况下促进与转录激活相关的组蛋白修饰。鉴于ALDH1A1催化RA的生物合成，我们得出结论，ALDH1A1通过激活RA信号通路促进POLQ表达。最后，使用临床相关的患者来源类器官（PDO）模型，我们发现药理抑制剂NCT - 505抑制ALDH1A1与PARP抑制剂奥拉帕利联合使用可协同降低携带BRCA1/2突变且ALDH1A1表达阳性的PDO的细胞活力。总之，我们的研究阐明了HR缺陷型卵巢癌对PARPi耐药的一种新机制，并显示了联合使用PARPi和抑制ALDH1A1治疗这些患者的治疗潜力。
