Cell Reports (Jun 2020)
Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers
- Irem Ozkan-Dagliyan,
- J. Nathaniel Diehl,
- Samuel D. George,
- Antje Schaefer,
- Bjoern Papke,
- Kathleen Klotz-Noack,
- Andrew M. Waters,
- Craig M. Goodwin,
- Prson Gautam,
- Mariaelena Pierobon,
- Sen Peng,
- Thomas S.K. Gilbert,
- Kevin H. Lin,
- Onur Dagliyan,
- Krister Wennerberg,
- Emanuel F. Petricoin, III,
- Nhan L. Tran,
- Shripad V. Bhagwat,
- Ramon V. Tiu,
- Sheng-Bin Peng,
- Laura E. Herring,
- Lee M. Graves,
- Christine Sers,
- Kris C. Wood,
- Adrienne D. Cox,
- Channing J. Der
Affiliations
- Irem Ozkan-Dagliyan
- 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
- Samuel D. George
- Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Antje Schaefer
- Department of Pharmacology, 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
- Kathleen Klotz-Noack
- Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, 10117 Berlin, Germany
- Andrew M. Waters
- 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
- Prson Gautam
- Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland
- Mariaelena Pierobon
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
- Sen Peng
- Departments of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
- Thomas S.K. Gilbert
- UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Kevin H. Lin
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
- Onur Dagliyan
- Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
- Krister Wennerberg
- Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland
- Emanuel F. Petricoin, III
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
- Nhan L. Tran
- Departments of Cancer Biology and Neurosurgery, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA
- Shripad V. Bhagwat
- Eli Lilly and Company, Indianapolis, IN 46285, USA
- Ramon V. Tiu
- Eli Lilly and Company, Indianapolis, IN 46285, USA
- Sheng-Bin Peng
- Eli Lilly and Company, Indianapolis, IN 46285, USA
- Laura E. Herring
- UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lee M. Graves
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Christine Sers
- Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Berlin Institute of Health (BIH), Anna-Louise-Karsch-Str. 2, 10178 Berlin, Germany
- Kris C. Wood
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
- Adrienne D. Cox
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, 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
- 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; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, 10117 Berlin, Germany; Corresponding author
- Journal volume & issue
-
Vol. 31,
no. 11
p. 107764
Abstract
Summary: We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF (RAFi) and ERK (ERKi), is highly synergistic at low doses in cell line, organoid, and rat models of PDAC, whereas each inhibitor alone is only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA) pathway mapping and RNA sequencing (RNA-seq) show that RAFi/ERKi induced insensitivity to loss of negative feedback and system failures including loss of ERK signaling, FOSL1, and MYC; shutdown of the MYC transcriptome; and induction of mesenchymal-to-epithelial transition. We conclude that low-dose vertical inhibition of the RAF-MEK-ERK cascade is an effective therapeutic strategy for KRAS mutant PDAC.
