Anti-tumor Activity Of CUDC-907, A Novel HDAC/PI3K Dual Inhibitor In Pancreatic Cancer

Pancreatic cancer is a malignant tumor of digestive tract with the characteristics of lack of early detection methods, high rate of relapse, and limited effective therapies. The incidence and mortality rates of pancreatic cancer have been increasing year by year in China. Surgery is the best option for these patients. However, it is often diagnosed lately due to the deep location of pancreas in the abdominal cavity, resulting in its low resection rate. Chemotherapy is the main treatment for pancreatic cancer. Gemcitabine, a nucleoside analogue, is the standard first-line drug for treating patients with advanced pancreatic cancer. However, its efficacy remains low. Therefore, new therapeutic targets and approaches are urgently needed.Genomic change is an important factor causing cancer, but also provides a target for the treatment of cancer. Histone deacetylases(HDACs) modify the structure of chromatin through altering the acetylation status of histone and non-histone proteins and affect the expression of target genes. Aberrant HDAC expression has been found in pancreatic cancer. Because of its ability to reverse epigenetic abnormalities involved in cancer onset and progression, HDACs have been developed for therapeutic targets. PI3 kinases(PI3Ks), an important intracellular protein kinase family, convert their substrate PIP2(phosphatidylinositol4,5-biphosphate) into its triple-phosphorylated form PIP3(phosphatidylinositol(3,4,5)-triphosphate). Subsequently, PIP3 activates downstream protein AKT and m TOR, causing cell proliferation and anti-apoptosis. Therefore, PI3 Ks also become important targets for cancer therapy.CUDC-907 is a novel, dual-acting small molecule compound designed to simultaneously inhibit the activity of HDACs and PI3 Ks. It has been estimated to be a potential anti-tumor drug for B cell lymphoma or multiple myeloma. Its anti-tumor activity and mechanism of action in pancreatic cancer have not been reported yet. We investigated the anti-tumor activity of CUDC-907 in pancreatic cancer in vitro and in vivo, and selected some small molecule inhibitors enhancing the efficacy according to mechanism of its action. The results are helpful for providing the new pathway for cotreatment of pancreatic cancer with CUDC-907 and other inhibitors.First, we investigated the anti-tumor activity of CUDC-907 in pancreatic cancer cell lines and xenograft mouse model. The results showed that CUDC-907 inhibited pancreatic cancer cell growth and induced cell apoptosis in a dose-dependent manner. In a Bx PC-3 xenograft mouse model, CUDC-907 significantly inhibited the growth of tumor compared to vehicle group. Body weights remained relatively the same throughout the study, regardless of treatment group, indicating that the drugs were well tolerated. To further investigate the in vivo effects of CUDC-907 treatment, tumors were analyzed by H&E, immunohistochemical, and TUNEL staining. The results showed that CUDC-907 increased tumor necrosis as indicated by H&E staining, inhibited cell proliferation as indicated by lower PCNA and VEGF staining, promoted cell apoptosis as indicated by TUNEL assay. These data highlight the potential for using CUDC-907 for the treatment of pancreatic cancer.Further, we explored the molecular mechanism of cytotoxicity of CUDC-907 in pancreatic cancer cell lines. The results showed that CUDC-907 increased the phosphorylation level of S6 and ERK1/2, suggesting that CUDC-907 may activate m TOR1 and ERK1/2 by the negative feedback loop. Combination of CUDC-907 with m TORC1 inhibitor rapamycin, m TORC1/2 inhibitor KU-0063794, ERK1/2 inhibitor SCH772984 or PI3K/m TOR inhibitor VS-5584 resulted in synergistic antitumor activity in pancreatic cancer cells, respectively. It suggests that the negative feedback activation on the m TORC1 and ERK1/2 provides a potential mechanism of resistance to treatment with CUDC-907. These data provide a theoretical basis for promoting the antitumor activity of CUDC-907.In summary, CUDC-907 has antitumor activity in preclinical models of pancreatic cancer. A preliminary study of the mechanism of action also provides a theoretical basis to further improve its antitumor activity. The results support the clinical development of CUDC-907 for the treatment of pancreatic cancer alone or in combination.