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

• 成果类型: Article
• 署名作者: Klomp, Jeffrey A.; Klomp, Jennifer E.; Stalnecker, Clint A.; Bryant, Kirsten L.; Edwards, A. Cole; Drizyte-Miller, Kristina; Hibshman, Priya S.; Diehl, J. Nathaniel; Lee, Ye S.; Morales, Alexis J.; Taylor, Khalilah E.; Peng, Sen; Tran, Nhan L.; Herring, Laura E.; Prevatte, Alex W.; Barker, Natalie K.; Hover, Laura D.; Hallin, Jill; Chowdhury, Saikat; Coker, Oluwadara; Lee, Hey Min; Goodwin, Craig M.; Gautam, Prson; Olson, Peter; Christensen, James G.; Shen, John P.; Kopetz, Scott; Graves, Lee M.; Lim, Kian-Huat; Wang-Gillam, Andrea; Wennerberg, Krister; Cox, Adrienne D.; Der, Channing J.
• 署名单位: University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Illumina; Mayo Clinic; Mayo Clinic Phoenix; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Mirati Therapeutics, Inc.; University of Texas System; UTMD Anderson Cancer Center; University of Helsinki; Washington University (WUSTL); University of Copenhagen; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11629
• DOI: 10.1126/science.adk0775
• 发表日期: 2024-06-07
• 关键词: oncogenic kras; acquired-resistance; inhibition; ras; degradation; phosphorylation; bioconductor; kras(g12d); efficacy; database

摘要

How the KRAS 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.