The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer
- J Exp Clin Cancer Res. 2020 Oct 17;39(1):219. doi: 10.1186/s13046-020-01728-2.
- 1. High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.
- 2. University of Science and Technology of China, Hefei, 230026, Anhui, P. R. China.
- 3. Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.
- 4. High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China. [email protected].
- 5. Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China. [email protected].
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.