Abstract 3829: Preclinical development of a combination inhibitor strategy to block K-Ras effector signaling and autophagy for pancreatic cancer treatment

Pancreatic cancer is the 4th leading cause of cancer deaths in the US and the 5-year survival rate is a dismal 6%. The KRAS oncogene is mutated in ∼95% of pancreatic ductal adenocarcinoma (PDAC) and targeting KRAS is one of four key priorities for pancreatic cancer research, as outlined by the NCI. We hypothesize that inhibition of K-Ras effector signaling is the most promising approach to achieve this goal, and that concurrent inhibition of mutant KRAS-mediated metabolic reprogramming, in particular upregulated autophagy, is needed to disrupt resistance mechanisms that render PDAC cells unaffected by inhibition of either pathway alone. Our preliminary data show that PDAC cells increase levels of autophagic signaling upon KRAS silencing as a compensatory mechanism for the cell to maintain anabolic processes, particularly due to the loss of upregulated glycolytic signaling and macropincytotic scavenging. Furthermore, we show that ERK inhibitor treatment, just like KRAS silencing, increases autophagic flux in PDAC cells. Additionally, we have demonstrated in vitro that chloroquine (CQ), an inhibitor of autophagy, synergistically enhances the anti-proliferative capacity of two different ERK inhibitors, one of which is under clinical evaluation. Finally, we show that signaling pathways that promote resistance to ERK inhibitor treatment alone are incapable of promoting resistance to the combination treatment with CQ. Overall, our studies support the further clinical evaluation of duel ERK and autophagy inhibition as a treatment for PDAC. Citation Format: Kirsten L. Bryant, Tikvah K. Hayes, Daniel Zeitouni, Samuel D. George, Swapnil Kher, Ahmed A. Samatar, Kris C. Wood, Alec C. Kimmelman, Channing J. Der. Preclinical development of a combination inhibitor strategy to block K-Ras effector signaling and autophagy for pancreatic cancer treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3829.