Dual HDAC and PI3K Inhibitor CUDC-907 Inhibits Growth of Pleural Mesothelioma: The Impact of Cisplatin Sensitivity and Myc Expression

<b>Objectives:</b> Pleural mesothelioma (PM) is a rare cancer that often develops after a decades-long latency period and confers a grim prognosis. Novel, biomarker-based therapeutic modalities are expected to improve the outcome of patients with advanced PM. CUDC-907 (fimepinostat) is a dual inhibitor that affects both histone deacetylases and PI3K enzymes. Its antitumor activity was described in several cancer types, but it has not yet been explored in PM. <b>Materials and Methods:</b> The sensitivity of 22 PM cell lines-including 18 models established in our laboratory-to cisplatin and CUDC-907 was determined using a cell viability assay. BAP1, PTEN, and c-Myc expression, as well as <i>MYC</i> copy number variation, were measured. The effect of combination treatment with cisplatin was assessed with cell viability, cell cycle, and 3D spheroid formation assays. <b>Results:</b> Most PM cell lines were sensitive to CUDC-907 treatment, and the CUDC-907 response was significantly higher in cell lines with higher c-Myc expression due to <i>MYC</i> copy number gain or amplification. Importantly, all cisplatin-insensitive cell lines were sensitive to CUDC-907. Combination treatment with cisplatin synergistically decreased cell viability and induced G2/M arrest or cell death. We tested cisplatin-sensitive P31WT and cisplatin resistant P31cis isogeneic pair and found that in both 2D and 3D assays the cisplatin-resistant cells showed a higher sensitivity to CUDC-907 single treatment. Combining CUDC-907 with cisplatin further decreased cell growth even in cisplatin-resistant cells. <b>Conclusions:</b> The majority of PM cell models are sensitive to CUDC-907, which may be a potent therapeutic agent in PM.