CASP1 is a target for combination therapy in pancreatic cancer

Gemcitabine (GEM) is commonly used as the first-line chemotherapeutic agent for treating pancreatic cancer (PC) patients. However, drug resistance is a major hurdle in GEM-based chemotherapy for PC. Recent studies have shown that pyroptosis, a type of programmed death, plays a significant regulatory role in cancer development and therapy. In this study, we observed an increase in the expression of Caspase-1(CASP1)/Gasdermin-D (GSDMD) in PC and found that high expression of CASP1 and GSDMD was associated with poor overall survival (OS) and progression-free survival (PFS) of PC patients. Knockdown of either CASP1 or GSDMD resulted in the inhibition of cell viability and migration in PC cells. More importantly, the knockdown of CASP1 or GSDMD enhanced GEM-induced cell death in PC cells. Interestingly, subsequent investigations demonstrated that enzymatically active CASP1 promoted GEM-induced cell death in PC cells. The activation of CASP1 by the DPP8/DPP9 inhibitor (Val-boroPro, VbP) increased GEM-induced cell death by inducing pyroptosis. These findings suggest that inhibiting CASP1 to suppress its oncogenic effects or activating it to promote cell pyroptosis both enhance the sensitivity of PC cells to GEM therapy.