Anti-apoptotic protein inhibitors sensitize pancreatic cancer cells to chemotherapies
Despite being the 14th most common cancer diagnosis, pancreatic cancer is the 3rd largest cause of cancer deaths in the United States, with a 5-year survival rate of <13%. The other two leading causes both have validated diagnostic tests, contrasting with pancreatic cancer, which has none. Without a diagnostic test or distinctive symptoms, it is often diagnosed at a late stage when the disease has spread to other organs. In addition, pancreatic cancer is difficult to treat because the fibrotic tumor microenvironment decreases blood flow to the area, impeding drug delivery. Pancreatic ductal adenocarcinoma (PDAC), which accounts for >90% of all pancreatic cancer cases, is highly resistant to chemotherapy and targeted treatments. One mechanism PDAC cells use to resist drug treatment is upregulating anti-apoptotic proteins such as BCL-2 and BCL-xL. This study explores potential synergisms between two inhibitors of these proteins, venetoclax and navitoclax, and the standard of care chemotherapeutic drugs, gemcitabine and nab-paclitaxel, to investigate a potential clinical combination. We hypothesized that inhibiting BCL-2 with venetoclax or both BCL-2 and BCL-xL with navitoclax could lead to greater apoptotic cell death induced by chemotherapeutic drugs. Our results demonstrated that there were significant synergistic activities between the drugs in supressing PDAC cancer cell growth. Future studies will focus on validating the synergism in animal modles.
