Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, PR China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China; Tianjin's Clinical Research Center for Cancer, PR China; Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin, 300060, PR China.
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, PR China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, PR China.
Cancer Lett. 2021 Apr 10;503:197-212. doi: 10.1016/j.canlet.2021.01.008. Epub 2021 Jan 23.
Patient mortality rates have remained stubbornly high for the past decades in small cell lung cancer (SCLC) because of having no standard targeted therapies with confirmed advantages at present. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models but have had unsatisfactory clinical results in SCLC. By RNA-seq and isobaric tags for relative and absolute quantification (ITRAQ), we revealed that PARP1 inhibition led to the relocalization of forkhead box-O3a (FOXO3a) from nuclear to cytoplasm. By performing co-Immunoprecipitation (co-IP) and CRISPR-Cas9-mediated knockout plasmid we showed that FOXO3a was subject to exportin 1 (XPO1)-dependent nuclear export. We demonstrated the effects of the PARP inhibitor BMN673 on apoptosis and DNA damage were markedly enhanced by simultaneous inhibition of XPO1 in vitro. The combination of BMN673 and the XPO1 inhibitor selinexor inhibited primary SCLC cell proliferation in mini-patient-derived xenotransplants (miniPDXs) and markedly inhibited tumor growth without significant toxicity in xenograft models. The efficacy was enhanced for more than 2.5 times, compared to the single agent. Based on these findings, we further designed a novel dual PARP-XPO1 inhibitor and showed its effectiveness in SCLC. In this work, we illustrated that combining a PARP inhibitor with an XPO1 inhibitor is associated with significantly improved efficacy and tolerability. Dual PARP-XPO1 inhibition restored the FOXO3a balance and activity in SCLC. Collectively, targeting PARP1 and XPO1 opens new avenues for therapeutic intervention against SCLC, warranting further investigation in potential clinical trials.
在过去的几十年中，由于目前没有标准的靶向治疗方法具有明确的优势，小细胞肺癌（SCLC）患者的死亡率一直居高不下。聚[ADP-核糖]聚合酶（PARP）抑制剂在临床前模型中显示出了前景，但在 SCLC 中的临床结果并不令人满意。通过 RNA-seq 和相对和绝对定量的同重同位素标记（ITRAQ），我们揭示了 PARP1 抑制导致叉头框 O3a（FOXO3a）从核内重新定位到细胞质。通过进行共免疫沉淀（co-IP）和 CRISPR-Cas9 介导的敲除质粒，我们表明 FOXO3a 受核输出蛋白 1（XPO1）依赖性核输出的影响。我们证明了 PARP 抑制剂 BMN673 在体外同时抑制 XPO1 时，对细胞凋亡和 DNA 损伤的作用明显增强。BMN673 与 XPO1 抑制剂 selinexor 的联合抑制了迷你患者来源异种移植（miniPDXs）中原发性 SCLC 细胞的增殖，并在异种移植模型中显著抑制了肿瘤生长而没有明显的毒性。与单药相比，疗效增强了 2.5 倍以上。基于这些发现，我们进一步设计了一种新型的双重 PARP-XPO1 抑制剂，并证明了其在 SCLC 中的有效性。在这项工作中，我们说明了将 PARP 抑制剂与 XPO1 抑制剂联合使用与显著改善的疗效和耐受性相关。双重 PARP-XPO1 抑制恢复了 SCLC 中 FOXO3a 的平衡和活性。总的来说，针对 PARP1 和 XPO1 为治疗 SCLC 开辟了新的途径，值得在潜在的临床试验中进一步研究。
