CUDC-907 exerts an inhibitory effect on non-small cell lung cancer associated with induction of mitotic catastrophe and downregulation of YAP/TAZ signaling

Non-small cell lung Cancer (NSCLC) is the most common histologic subtype of lung Cancer associated with a relatively high mortality rate. CUDC-907, a dual-target inhibitor of histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K), has the potential to suppress the progression of various malignancies. However, the anti-cancer effect of CUDC-907 on NSCLC remains to be fully elucidated. In this study, we explored the anti-NSCLC effects of CUDC-907 and the possible underlying mechanisms. NSCLC cells were treated with different concentrations of CUDC-907, and cell viability was detected using the Cell Counting Kit-8 (CCK-8) assay. Cell proliferation was evaluated using colony formation and 5-ethynyl-2'-deoxyuridine (EdU) assays, while γ- H2A.X histone variant (H2AX) immunofluorescence was used to monitor DNA damage. The in vivo anti-tumor efficacy of CUDC-907 against NSCLC was evaluated using a xenograft mouse model, and protein expression levels were examined via Western blot analysis. The results revealed that CUDC-907 reduced the viability of A549 and H1299 cells in a concentration-dependent manner. Colony formation and EdU assays showed that CUDC-907 suppressed the proliferation of NSCLC cells. Exposure to CUDC-907 caused G2/M phase arrest in both A549 and H1299 cells by decreasing the expression of cyclin A, cell division cycle 25C (Cdc25C), p-Cdc25C, Cdc2, and cyclin B1, and increasing the protein levels of p21. Treatment with CUDC-907 induced γ-H2AX foci formation and abnormal Mitosis in NSCLC cells by downregulating the expression of Aurora A, Aurora B, and polo-like kinase 1 (PLK1). In addition, CUDC-907 triggered A549 and H1299 cell Apoptosis by increasing the cleavage of Caspase-3, Caspase-8, caspase-9, and poly (ADP-ribose) polymerase (PARP). Mechanistic studies revealed that CUDC-907 activated inositol-requiring enzyme 1 α (IRE1α)-c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) pathway, and blocked -Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling in A549 and H1299 cells. Additionally, CUDC-907 treatment significantly inhibited tumor growth and reduced tumor weight in the tumor xenograft mouse model. Taken together, this study revealed the cytotoxic effects of CUDC-907 and its underlying mechanism, which suggests that CUDC-907 may be an effective therapeutic approach for treating NSCLC.

CUDC-907; DNA damage; Mitotic catastrophe; NSCLC; YAP.