e14591 Background: 93% of pancreatic cancers have activating mutations in the K-Ras gene. We have previously shown that mutated, constitutively-activated Ras is lethal to cells if an essential Ras-driven survival pathway is disrupted by suppression of PKCδ. PKCδ has various cellular functions, but is not required for the survival of normal cells and its inhibition in vitro or in vivo has no known adverse effects. Signal transducer and activator of transcription 3 (STAT3) is constitutive driver of many solid cancers, including pancreatic cancers. STAT3 requires phosphorylation of Tyr 705 for activation and, once activated translocates to the nucleus, where it controls genes involved in cell survival or death. Methods: Human pancreatic cancer cell lines PancI, MIAPACA and primary human pancreatic cancer stem cells were studied. shRNA-mediated knockdown of PKCδ, with scrambled shRNA as a control, was used to validate PKCδ as a target. Rottlerin and KAM1 were used as relatively specific PKCδ inhibitors. For inhibition of STAT3, specific shRNA against STAT3 versus scrambled shRNA were employed for knock-downs. For cytotoxicity analyses, MTS assays were used to assess cell growth. Z-vad-FMK was used as a pan-caspase inhibitor. Immunoblotting was used to verify knock-down of PKCδ or STAT3 and to quantify the phosphorylation status of STAT3 phospho-Tyr 705. Results: PKCδ inhibition by either shRNA knock-down or inhibitor led to dephosphorylation of STAT3 at Tyr 705, extensive cytotoxicity of pancreatic cancer cells and dramatic reductions in tumor clonogenic capacity. Knock down of STAT3 was equally cytotoxic to pancreatic cancer cells. Cytotoxicity following PKCδ inhibition was not prevented by a pan-caspase inhibitor. Conclusions: Activated STAT3 and survival in pancreatic cancer cells requires PKCδ. Inhibition of PKCδ, and subsequent suppression of STAT3 activation, is cytotoxic for pancreatic cancer cells through a mechanism independent of caspase activation or apoptosis. Small molecule inhibitors of PKCδ have potential as targeted therapeutic agents against pancreatic tumors, pancreatic cancer stem cells, and other human tumors with mutational activation of Ras.