Cell Reports (Jun 2021)
Targeting p130Cas- and microtubule-dependent MYC regulation sensitizes pancreatic cancer to ERK MAPK inhibition
- Andrew M. Waters,
- Tala O. Khatib,
- Bjoern Papke,
- Craig M. Goodwin,
- G. Aaron Hobbs,
- J. Nathaniel Diehl,
- Runying Yang,
- A. Cole Edwards,
- Katherine H. Walsh,
- Rita Sulahian,
- James M. McFarland,
- Kevin S. Kapner,
- Thomas S.K. Gilbert,
- Clint A. Stalnecker,
- Sehrish Javaid,
- Anna Barkovskaya,
- Kajal R. Grover,
- Priya S. Hibshman,
- Devon R. Blake,
- Antje Schaefer,
- Katherine M. Nowak,
- Jennifer E. Klomp,
- Tikvah K. Hayes,
- Michelle Kassner,
- Nanyun Tang,
- Olga Tanaseichuk,
- Kaisheng Chen,
- Yingyao Zhou,
- Manpreet Kalkat,
- Laura E. Herring,
- Lee M. Graves,
- Linda Z. Penn,
- Hongwei H. Yin,
- Andrew J. Aguirre,
- William C. Hahn,
- Adrienne D. Cox,
- Channing J. Der
Affiliations
- Andrew M. Waters
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Tala O. Khatib
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Bjoern Papke
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Craig M. Goodwin
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- G. Aaron Hobbs
- 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
- J. Nathaniel Diehl
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Runying Yang
- 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
- A. Cole Edwards
- 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
- Katherine H. Walsh
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Rita Sulahian
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- James M. McFarland
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Kevin S. Kapner
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Thomas S.K. Gilbert
- 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
- Clint A. Stalnecker
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Sehrish Javaid
- Oral and Craniofacial Biomedicine PhD Program, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Anna Barkovskaya
- Institute for Cancer Research, Oslo University Hospital, Oslo 0379, Norway
- Kajal R. Grover
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Priya S. Hibshman
- 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
- Devon R. Blake
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Antje Schaefer
- 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
- Katherine M. Nowak
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Jennifer E. Klomp
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Tikvah K. Hayes
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Michelle Kassner
- Cancer and Cell Biology Division, Translational Genomic Research Institute, Phoenix, AZ 85004, USA
- Nanyun Tang
- Cancer and Cell Biology Division, Translational Genomic Research Institute, Phoenix, AZ 85004, USA
- Olga Tanaseichuk
- Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
- Kaisheng Chen
- Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
- Yingyao Zhou
- Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
- Manpreet Kalkat
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5S, Canada
- Laura E. Herring
- UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lee M. Graves
- 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
- Linda Z. Penn
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5S, Canada
- Hongwei H. Yin
- Cancer and Cell Biology Division, Translational Genomic Research Institute, Phoenix, AZ 85004, USA
- Andrew J. Aguirre
- 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
- William C. Hahn
- 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
- Adrienne D. Cox
- 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 North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Channing J. Der
- 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 Hill, Chapel Hill, NC 27599, USA; Oral and Craniofacial Biomedicine PhD Program, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Corresponding author
- Journal volume & issue
-
Vol. 35,
no. 13
p. 109291
Abstract
Summary: 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-β-catenin-dependent mechanism. Additionally, genetic suppression of TUBB3, encoding the βIII-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.
