Rucaparib, a PARP inhibitor, enhances β-lapachone-induced pyroptosis in pancreatic cancer cells

Abstract

β-lapachone (β-lap) is FDA-approved to be used in a clinical trial. Efficacy of β-lap associates with cancer cell death and alterations in the tumor immune microenvironment. However, the links are poorly understood. We show that β-lap treatment triggered caspase 1 activity, promoted cleavage of gasdermin D (GSDMD), and released IL-1β and IL-18, markers of pyroptotic cell death. To expand the therapeutic utility of β-lap, we here demonstrate the combination of β-lap with Rucaparib, a PARP inhibitor in NQO1+ pancreatic cancer cells. Rucaparib enhances β-lap lethality and activates gasdermin E/caspase 3- mediated pyroptosis. These data implicate β-lap-induced pyroptosis in anti-tumor immune responses and highlight new therapeutic strategies for resistant PDA.