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Targeting p130Cas- and microtubule-dependent MYC regulation sensitizes pancreatic cancer to ERK MAPK inhibition.
Waters, Andrew M; Khatib, Tala O; Papke, Bjoern; Goodwin, Craig M; Hobbs, G Aaron; Diehl, J Nathaniel; Yang, Runying; Edwards, A Cole; Walsh, Katherine H; Sulahian, Rita; McFarland, James M; Kapner, Kevin S; Gilbert, Thomas S K; Stalnecker, Clint A; Javaid, Sehrish; Barkovskaya, Anna; Grover, Kajal R; Hibshman, Priya S; Blake, Devon R; Schaefer, Antje; Nowak, Katherine M; Klomp, Jennifer E; Hayes, Tikvah K; Kassner, Michelle; Tang, Nanyun; Tanaseichuk, Olga; Chen, Kaisheng; Zhou, Yingyao; Kalkat, Manpreet; Herring, Laura E; Graves, Lee M; Penn, Linda Z; Yin, Hongwei H; Aguirre, Andrew J; Hahn, William C; Cox, Adrienne D; Der, Channing J.
Afiliação
  • Waters AM; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Khatib TO; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Papke B; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Goodwin CM; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Hobbs GA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Diehl JN; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Yang R; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Edwards AC; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Walsh KH; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Sulahian R; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • McFarland JM; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Kapner KS; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Gilbert TSK; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Michael Hooker Proteomics Center, 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.
  • Javaid S; Oral and Craniofacial Biomedicine PhD Program, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Barkovskaya A; Institute for Cancer Research, Oslo University Hospital, Oslo 0379, Norway.
  • Grover KR; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Hibshman PS; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Blake DR; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Schaefer A; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Nowak KM; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Klomp JE; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Hayes TK; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Kassner M; Cancer and Cell Biology Division, Translational Genomic Research Institute, Phoenix, AZ 85004, USA.
  • Tang N; Cancer and Cell Biology Division, Translational Genomic Research Institute, Phoenix, AZ 85004, USA.
  • Tanaseichuk O; Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
  • Chen K; Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
  • Zhou Y; Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
  • Kalkat M; Department of Medical Biophysics, University of Toronto, Toronto, ON M5S, Canada.
  • Herring LE; UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Graves LM; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Penn LZ; Department of Medical Biophysics, University of Toronto, Toronto, ON M5S, Canada.
  • Yin HH; Cancer and Cell Biology Division, Translational Genomic Research Institute, Phoenix, AZ 85004, USA.
  • Aguirre AJ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Brigham and Women's Hospital, Boston, MA 02215, USA.
  • Hahn WC; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Brigham and Women's Hospital, Boston, MA 02215, USA.
  • Cox AD; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Oral and Craniofacial Biomedicine PhD Program, School of Dentistry, University of Nort
  • Der CJ; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel H
Cell Rep ; 35(13): 109291, 2021 06 29.
Article em En | MEDLINE | ID: mdl-34192548
ABSTRACT
To identify therapeutic targets for KRAS mutant pancreatic cancer, we conduct a druggable genome small interfering RNA (siRNA) screen and determine that suppression of BCAR1 sensitizes pancreatic cancer cells to ERK inhibition. Integrative analysis of genome-scale CRISPR-Cas9 screens also identify BCAR1 as a top synthetic lethal interactor with mutant KRAS. BCAR1 encodes the SRC substrate p130Cas. We determine that SRC-inhibitor-mediated suppression of p130Cas phosphorylation impairs MYC transcription through a DOCK1-RAC1-ß-catenin-dependent mechanism. Additionally, genetic suppression of TUBB3, encoding the ßIII-tubulin subunit of microtubules, or pharmacological inhibition of microtubule function decreases levels of MYC protein in a calpain-dependent manner and potently sensitizes pancreatic cancer cells to ERK inhibition. Accordingly, the combination of a dual SRC/tubulin inhibitor with an ERK inhibitor cooperates to reduce MYC protein and synergistically suppress the growth of KRAS mutant pancreatic cancer. Thus, we demonstrate that mechanistically diverse combinations with ERK inhibition suppress MYC to impair pancreatic cancer proliferation.
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Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Proteínas Proto-Oncogênicas c-myc / MAP Quinases Reguladas por Sinal Extracelular / Inibidores de Proteínas Quinases / Proteína Substrato Associada a Crk / Microtúbulos Limite: Humans Idioma: En Revista: Cell Rep Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
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Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Proteínas Proto-Oncogênicas c-myc / MAP Quinases Reguladas por Sinal Extracelular / Inibidores de Proteínas Quinases / Proteína Substrato Associada a Crk / Microtúbulos Limite: Humans Idioma: En Revista: Cell Rep Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos