Abstract SY20-02: Inhibitor combinations targeting KRAS effector signaling in KRAS-mutant pancreatic cancer

KRAS mutations are found in 95% of pancreatic ductal adenocarcinoma (PDAC), where they are key cancer drivers. Effective anti-KRAS therapeutics are thus anticipated to make a significant improvement in PDAC treatment. Despite the promise of inhibiting KRAS effector signaling, such inhibitors have not demonstrated significant activity as monotherapy, and there are concerns regarding potential normal tissue toxicity. Inhibitor combinations may overcome limitations of both efficacy and toxicity. We performed a 525-drug chemical biology screen to identify combinations that enhanced the cytotoxic activity of inhibitors of the RAF-MEK-ERK and the PI3K-AKT-mTOR effector pathways. Many such combinations were identified for RAF effector pathway inhibitors, while few were identified for PI3K pathway inhibitors. Generally, the same classes of inhibitors were identified for inhibitors of the RAF, MEK, and ERK nodes of the MAP kinase (MAPK) cascade. We found that inhibitors of the PI3K-AKT-mTOR pathway, microtubules, HDAC, and HSP90 each synergistically enhanced the cytotoxicity of RAF, MEK, and ERK inhibitors, in both conventional and PDX-derived PDAC cell lines. Mechanistically, we found that a shared basis for this synergy was enhanced loss of MYC protein, a key ERK substrate. Our studies identify promising combinations of KRAS effector inhibitors for PDAC treatment. Citation Format: Adrienne D. Cox, Craig M. Goodwin, Kirsten L. Bryant, Irem Dagliyan, Samuel D. George, Kelly E. Lucas, Prson Gautam, Krister Wennerberg, Channing J. Der. Inhibitor combinations targeting KRAS effector signaling in KRAS -mutant pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY20-02.