Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive, highly lethal form of cancer with a five-year survival rate of only 7%. More than 90% of PDAC cases are driven by a mutation in the KRAS gene, which encodes a protein that activates the mitogen-activated protein kinase (MAPK) pathway. Although selective inhibitors targeting KRAS as well as downstream MAPK pathway members BRAF, MEK, and ERK have been developed, clinical efficacy of these drugs either alone or in combination has been limited due to the ability of cancer cells to develop resistance. Measurement of ERK phosphorylation is often used to assess engagement of the pathway by these inhibitors. However, ERK activation regulates MAPK pathway signaling through multiple divergent downstream phosphorylation events that lead to changes in cell cycle progression, proliferation, apoptosis, adhesion, metabolism, and other cellular outputs. Kevin Haigis and Andrew Aguirre of Dana-Farber Cancer Institute and Forest White of Massachusetts Institute of Technology have generated data that support the hypothesis that selective ERK target phosphorylation that differs by tissue, cellular, and/or genetic context(s) determines the variable responses to MAPK pathway inhibitors.
The goals of this project, led by Dr. Haigis, are to uncover how ERK2 phosphorylation target utilization is impacted by the genetic landscape of a tumor and to identify ERK2 phosphorylation targets that correlate with response to MAPK pathway inhibition. The team is applying state-of-the-art mass spectrometry methods to tumors from genetically engineered mouse models and patient-derived PDAC organoids to comprehensively define ERK phosphorylation targets and identify those that correlate with response to MAPK inhibitors. The results of this research will refine our understanding of MAPK signaling output and inhibitor efficacy based on ERK2 downstream target phosphorylation rather than measuring changes in phosphorylation of ERK2 alone. The application of innovative mass spectrometry techniques to drive conceptual advances in knowledge of context-specific ERK2 phosphorylation target utilization will provide a novel set of clinically relevant biomarkers to predict and monitor clinical response to MAPK inhibitors and inform therapeutic adjustments in response to emergence of drug resistance.