High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.
University of Science and Technology of China, Hefei, 230026, Anhui, P. R. China.
J Exp Clin Cancer Res. 2020 Oct 17;39(1):219. doi: 10.1186/s13046-020-01728-2.
Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor with limited therapeutic options. Recent data suggest that histone deacetylases (HDACs) and the phosphatidylinositol 3-kinase (PI3K) pathway play essential roles in SCLC cell proliferation and survival.
The inhibition of the PI3K signaling and HDAC activity by CUDC-907 was analyzed by western blotting. The effect of CUDC-907 on olaparib-induced DNA damage response was assessed by western blotting and Immunofluorescence staining. The cytotoxicity of CUDC-907 alone or in combination with olaparib in a panel of SCLC cell lines were evaluated by the CellTiter-Glo Luminescent Cell Viability Assay and flow cytometry. The in vivo effects of CUDC-907 and olaparib alone or in combination were examined using a patient-derived xenografts (PDX) model of SCLC.
CUDC-907 treatment downregulated MYC paralogs and FoxM1, induced G1 cell-cycle arrest, and impaired DNA double-strand break (DSB) repair capacity in SCLC cells, which produced a potent antiproliferative effect. Furthermore, we showed that CUDC-907 treatment enhanced the therapeutic efficacy of PARP inhibitor olaparib in SCLC cellular models and a PDX model. Mechanistic investigations demonstrated that CUDC-907 synergized with olaparib through the blockade of DSB repair pathways and downregulation of MYC paralogs and FoxM1.
Our study uncovers that dual PI3K and HDAC inhibition by CUDC-907 exerts significant single-agent activity and strong synergistic effects with PARP inhibitor olaparib in SCLC, which thus provides a rational combination treatment strategy for SCLC clinical investigation.
小细胞肺癌（SCLC）是一种致命的神经内分泌肿瘤，治疗选择有限。最近的数据表明，组蛋白去乙酰化酶（HDACs）和磷脂酰肌醇 3-激酶（PI3K）通路在 SCLC 细胞增殖和存活中发挥重要作用。
通过 Western blot 分析 CUDC-907 对 PI3K 信号和 HDAC 活性的抑制作用。通过 Western blot 和免疫荧光染色评估 CUDC-907 对奥拉帕利诱导的 DNA 损伤反应的影响。通过 CellTiter-Glo 发光细胞活力测定法和流式细胞术评估 CUDC-907 单独或与奥拉帕利联合在一系列 SCLC 细胞系中的细胞毒性。使用 SCLC 的患者来源异种移植（PDX）模型研究 CUDC-907 和奥拉帕利单独或联合的体内作用。
CUDC-907 处理下调了 MYC 同源物和 FoxM1，诱导了 SCLC 细胞的 G1 细胞周期停滞，并损害了 DNA 双链断裂（DSB）修复能力，从而产生了强大的抗增殖作用。此外，我们表明 CUDC-907 处理增强了 PARP 抑制剂奥拉帕利在 SCLC 细胞模型和 PDX 模型中的治疗效果。机制研究表明，CUDC-907 通过阻断 DSB 修复途径和下调 MYC 同源物和 FoxM1 与奥拉帕利协同作用。
我们的研究表明，CUDC-907 双重抑制 PI3K 和 HDAC 在 SCLC 中具有显著的单药活性，并与 PARP 抑制剂奥拉帕利具有强烈的协同作用，为 SCLC 的临床研究提供了合理的联合治疗策略。
