The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer

Liying Ma,Wenchu Lin,Xing Bian

doi:10.1186/s13046-020-01728-2

Abstract

BackgroundSmall 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.MethodsThe 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.ResultsCUDC-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.ConclusionsOur 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.

Highlights

Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor with limited therapeutic options
Small cell lung cancer cells are highly sensitive to dual HDAC and phosphatidylinositol 3-kinase (PI3K) inhibitor CUDC-907 As the PI3K signaling pathway and HDAC both are commonly dysregulated in SCLC cells, we wondered whether dual inhibition of phosphoinositide 3-kinase class I and pan histone deacetylase enzymes is effective in treating SCLC cells
A panel of SCLC cells was treated with increased concentrations of CUDC-907, a dual inhibitor of PI3K and HDAC, and the growth inhibitory effect of CUDC-907 was measured by CellTiter Glo assay after 3 days

Summary

Introduction

Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor with limited therapeutic options. Developing effective targeted options is a pressing clinical need to improved therapeutic benefits for patients with SCLC. In contrast to genetic mutations, the dynamic and reversible nature of epigenetic modifications makes epigenetic enzymes attractive to be harnessed for cancer therapy. Several epigenetic drugs such as histone deacetylase (HDAC) inhibitors showed promising anticancer activity and have been approved as anticancer agents by the FDA for hematological malignancies [6,7,8,9]. Previous studies have shown HDACi, as a single-agent or in combination with other small molecules, induces cell growth arrest, differentiation, and apoptosis in many cancer cell lines in vitro and in vivo, including SCLC [10,11,12,13]

Objectives

Methods

Results

Conclusion