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Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.
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; Sorokin, Alexey; Kanikarla, Preeti Marie; 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.
Afiliação
  • Klomp JA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Klomp JE; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Stalnecker CA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Bryant KL; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Edwards AC; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Drizyte-Miller K; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Hibshman PS; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Diehl JN; Cell Biology and Physiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Lee YS; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Morales AJ; Cell Biology and Physiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Taylor KE; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Peng S; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Tran NL; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Herring LE; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Prevatte AW; Illumina, Inc., San Diego, CA 92121, USA.
  • Barker NK; Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
  • Hover LD; Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Hallin J; Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Sorokin A; Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Kanikarla PM; Monoceros Biosystems LLC, San Diego, CA 92130, USA.
  • Chowdhury S; Mirati Therapeutics, Inc., San Diego, CA 92121, USA.
  • Coker O; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Lee HM; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Goodwin CM; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Gautam P; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Olson P; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Christensen JG; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Shen JP; Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
  • Kopetz S; Mirati Therapeutics, Inc., San Diego, CA 92121, USA.
  • Graves LM; Mirati Therapeutics, Inc., San Diego, CA 92121, USA.
  • Lim KH; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Wang-Gillam A; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Wennerberg K; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Cox AD; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Der CJ; Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
Science ; 384(6700): eadk0775, 2024 06 07.
Article em En | MEDLINE | ID: mdl-38843331
ABSTRACT
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Regulação Neoplásica da Expressão Gênica / Proteínas Proto-Oncogênicas p21(ras) / Sistema de Sinalização das MAP Quinases / Carcinoma Ductal Pancreático / MAP Quinases Reguladas por Sinal Extracelular / Transcriptoma / Mutação Limite: Animals / Humans Idioma: En Revista: Science Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Regulação Neoplásica da Expressão Gênica / Proteínas Proto-Oncogênicas p21(ras) / Sistema de Sinalização das MAP Quinases / Carcinoma Ductal Pancreático / MAP Quinases Reguladas por Sinal Extracelular / Transcriptoma / Mutação Limite: Animals / Humans Idioma: En Revista: Science Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos