Inhibition Of P38 Enhances Erk Inhibitor Efficacy In Pancreatic Ductal Adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the United States, with a poor prognosis and limited treatment options. Oncogenic mutation of KRAS in greater than 90% of PDAC leads to aberrant activation of multiple effector pathways including the extra cellular related kinase (ERK)/mitogen activated protein kinase (MAPK) cascade. Hyperactivation of the ERK MAPK cascade has been correlated with poorer prognosis in PDAC patients. We recently showed that direct pharmacological inhibition of ERK1/2 kinases with the ERK1/2-selective inhibitor SCH772984 inhibits the growth of PDAC cell lines both in vitro and in vivo. However, much like the response to ERK/MAPK pathway inhibitors acting at upstream nodes RAF or MEK, resistance to direct inhibition at the level of ERK will also inevitably arise. We performed a novel gain-of-function “Cancer Toolkit” (CTK) genetic screen to identify mechanisms of resistance to the ERK inhibitor SCH772984 in a panel of KRAS-mutant PDAC cell lines. Our CTK screen revealed that expression of either MAPK14 (p38α) or its upstream activator MKK6 could cause resistance to this and other ERK inhibitors. Because we identified activation of the p38 pathway as a mechanism of ERK inhibitor resistance, we tested whether inhibition of p38 would enhance sensitivity to SCH772984. We observed a >2 fold shift to a lower GI50 of SCH772984 upon cotreatment of a panel of established and patient-derived xenograft (PDX) PDAC cell lines with SCH772984 and the clinical candidate p38 inhibitor LY2228820. Consistent with this, we found that SCH772984 induced p38 signaling, marked by phosphorylation of the downstream substrate HSP27, and that combination treatment of SCH772984 and LY2228820 both reversed p38 pathway activation and enhanced PARP cleavage. Results of in vivo testing of the combination treatment as well as the mechanistic basis for p38-driven resistance will be reported. We propose that p38 is a mechanism of resistance to ERK inhibition in PDAC and that p38 inhibitors such as LY2228820 can overcome that resistance to enhance ERK inhibitor efficacy. Citation Format: Meagan B. Ryan, Kirsten L. Bryant, Tikvah K. Hayes, Swapnil Kher, Kris C. Wood, Ahmed A. Samatar, Adrienne D. Cox, Channing J. Der. Inhibition of p38 enhances ERK inhibitor efficacy in pancreatic ductal adenocarcinoma. [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 4660.