Mechanistic Basis for ERK in driving KRAS-dependent pancreatic cancer

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Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC), the third leading cause of cancer deaths in the United States, is characterized by a 95% rate of mutational activation of the KRAS oncogene. After nearly four decades of failure, the recent clinical approval of a direct KRAS inhibitor targeting one KRAS mutation (G12C) for lung cancer marks a significant milestone in the development of therapies for KRAS-mutant cancers. KRASG12C-specific inhibitors have demonstrated dramatic tumor shrinkage in a subset of KRASG12C-mutant patients but essentially all relapse due to treatment-induced acquired resistance. Genetic analyses of relapsed patients have identified mechanisms of resistance, with a majority involving mutational activation of signaling components that drive reactivation of the key KRAS effector pathway, the three-tiered RAF-MEK-ERK mitogen-activated protein kinase cascade. Thus, ERK reactivation will limit the long-term efficacy of direct KRAS inhibitors. Despite the highly successful development of potent and selective inhibitors of each node of the ERK MAPK cascade, when used as monotherapy, they have shown little to no clinical efficacy against RAS-mutant cancers. Two key issues have contributed to this outcome, toxicity for normal tissues and de novo or treatment-induced acquired resistance in cancer cells. I propose that further delineation of the mechanisms by which ERK drives KRAS-dependent cancer growth will guide the development of more effective anti-ERK therapies. However, the mechanisms by which ERK drives PDAC growth remain poorly understood. One major unresolved issue is how ERK activity in different subcellular compartments supports cancer growth. Aim 1 studies comprise my K99 phase of training where I will take two complementary approaches to gain a better understanding of the role of cytoplasmic and nuclear ERK activity in supporting KRAS-dependent PDAC growth. First, I will determine the capacity of cytoplasmic versus nuclear ERK activity in supporting the growth of KRAS-mutant PDAC. Second, I will use a pharmacological inhibitor of the nuclear export protein exportin-1 (Selinexor) to determine whether it disrupts ERK cytoplasmic- nuclear dynamics and sensitizes PDAC models to KRAS inhibition. My Aim 2 studies comprise my R00- supported independent research and are based on our comprehensive ERK-dependent phosphoproteome/ transcriptome studies in KRAS-mutant PDAC. Using these data, I designed a CRISPR-Cas9 genetic loss-of- function screen library, targeting ERK regulated phosphoproteins and/or transcripts. I will now perform a system- wide determination of how ERK contributes to PDAC tumorigenesis as well as identify new ERK dependent targets to combine with KRAS inhibitors. To help me achieve these research goals and successfully transition to the independent phase I have an exceptional mentoring committee comprised of leading researchers in the study of KRAS signaling and therapeutics (Channing Der), in ERK spatiotemporal signaling (Jin Zhang), and ERK substrate utilization (John Blenis). With their guidance I am confident that I will successfully transition to establish an independent research program where I will advance our knowledge on ERK signaling and therapeutics.