Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers

Jeffrey A. Klomp(University of North Carolina at Chapel Hill), Jeffrey A. Klomp(University of North Carolina at Chapel Hill), Jennifer E. Klomp(University of North Carolina at Chapel Hill), Jennifer E. Klomp(University of North Carolina at Chapel Hill), Clint A. Stalnecker(University of North Carolina at Chapel Hill), Kirsten L. Bryant(University of North Carolina at Chapel Hill), A. Cole Edwards(University of North Carolina at Chapel Hill), Kristina Drizyte‐Miller(University of North Carolina at Chapel Hill), Priya S. Hibshman(University of North Carolina at Chapel Hill), J. Nathaniel Diehl(University of North Carolina at Chapel Hill), Ye S. Lee(University of North Carolina at Chapel Hill), Alexis Jean Morales(University of North Carolina at Chapel Hill), Khalilah E. Taylor(University of North Carolina at Chapel Hill), Sen Peng(University of North Carolina at Chapel Hill), Nhan L. Tran(University of North Carolina at Chapel Hill), Laura E. Herring(University of North Carolina at Chapel Hill), Alex W. Prevatte(University of North Carolina at Chapel Hill), Natalie K. Barker(University of North Carolina at Chapel Hill), Laura D. Hover(The University of Texas MD Anderson Cancer Center), Jill Hallin(The University of Texas MD Anderson Cancer Center), Saikat Chowdhury(The University of Texas MD Anderson Cancer Center), Oluwadara Coker(University of North Carolina at Chapel Hill), Hey Min Lee(University of Helsinki), Craig M. Goodwin(University of North Carolina at Chapel Hill), Prson Gautam(University of Helsinki), Peter Olson(The University of Texas MD Anderson Cancer Center), James G. Christensen(The University of Texas MD Anderson Cancer Center), John Paul Shen(University of North Carolina at Chapel Hill), Scott Kopetz(The University of Texas MD Anderson Cancer Center), Lee M. Graves(University of North Carolina at Chapel Hill), Kian‐Huat Lim(University of Copenhagen), Andrea Wang‐Gillam(University of North Carolina at Chapel Hill), Krister Wennerberg(University of North Carolina at Chapel Hill), Adrienne D. Cox(University of North Carolina at Chapel Hill), Channing J. Der(University of North Carolina at Chapel Hill)
Science
June 6, 2024
10.1126/science.adk0775
Cited by 105Open Access
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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.

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