Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers
Jeffrey A. Klomp, Jeffrey A. Klomp, Jennifer E. Klomp, Jennifer E. Klomp, Clint A. Stalnecker, Kirsten L. Bryant, A. Cole Edwards, Kristina Drizyte‐Miller, Priya S. Hibshman, J. Nathaniel Diehl, Ye S. Lee, Alexis Jean Morales, Khalilah E. Taylor, Sen Peng, Nhan L. Tran, Laura E. Herring, Alex W. Prevatte, Natalie K. Barker, Laura D. Hover, Jill Hallin, Saikat Chowdhury, Oluwadara Coker, Hey Min Lee, Craig M. Goodwin, Prson Gautam, Peter Olson, James G. Christensen, John Paul Shen, Scott Kopetz, Lee M. Graves, Kian‐Huat Lim, Andrea Wang‐Gillam, Krister Wennerberg, Adrienne D. Cox, Channing J. Der
Abstract
oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.