ArticleCell reports2020
Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers.
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Article in Cell reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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68citing papers in PubMed
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Who cites it
68 citing papers in PubMed, 103 citations in OpenAlex.
- Protease-Activated Receptor-2 as a Proteolytic Rheostat in Colorectal and Pancreatic Cancer: From Mechanism to Biomarker-Guided Therapy.International journal of molecular sciences · 2026Review
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- Understanding and overcoming innate and acquired MAPK inhibition resistance in anaplastic thyroid cancer.Cell reports. Medicine · 2026Article
- Targeting RSK2 enhances the efficacy of IGF1R inhibitor against triple-negative breast cancer via antagonizing IGF1/IGF1R signaling mediated by GATA3-IGFBP5 pathway.Acta pharmacologica Sinica · 2026Article
- Dual inhibition of GTP-bound (ON) and GDP-bound (OFF) KRASbioRxiv : the preprint server for biology · 2026Article
- NPCDR 2.0: the activity and structure landscape of natural product-based drug combination.Nucleic acids research · 2026Article
- Patient-derived organoids guide personalized therapy for KRAS-mutant pancreatic cancer: synergistic MEK/mTOR inhibition and predictive chemotherapy responses.Frontiers in immunology · 2026Article
- KRAS: the Achilles' heel of pancreas cancer biology.The Journal of clinical investigation · 2025Review
- Concurrent Inhibition of the RAS-MAPK Pathway and PIKfyve Is a Therapeutic Strategy for Pancreatic Cancer.Cancer research · 2025Article
- Preclinical Activity of the Type II RAF Inhibitor Tovorafenib in Tumor Models Harboring Either a BRAF Fusion or an NF1 Loss-of-Function Mutation.Cancer research communications · 2025Article
- Pancreatic Cancer: Pathogenesis and Clinical Studies.MedComm · 2025Review
- Targeting Signaling Excitability in Cervical and Pancreatic Cancer Cells Through Combined Inhibition of FAK and PI3K.International journal of molecular sciences · 2025Article
- KRAS inhibitors: resistance drivers and combinatorial strategies.Trends in cancer · 2025Review
- Transforming cancer treatment: integrating patient-derived organoids and CRISPR screening for precision medicine.Frontiers in pharmacology · 2025Review
- Taurine Synthesis by 2-Aminoethanethiol Dioxygenase as a Vulnerable Metabolic Alteration in Pancreatic Cancer.Biomolecules & therapeutics · 2025Article
- Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy.Science translational medicine · 2024Article
- Article
- Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.Science (New York, N.Y.) · 2024Article
- Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer.Science (New York, N.Y.) · 2024Article
- A Histone Methylation-MAPK Signaling Axis Drives Durable Epithelial-Mesenchymal Transition in Hypoxic Pancreatic Cancer.Cancer research · 2024Article
8 more citing papers are in PubMed but not listed here.
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Authors and funding
26 authors at 9 institutions in 3 countries.
Irem Ozkan-DagliyanDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
J Nathaniel DiehlCurriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Samuel D GeorgeDepartment 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 SchaeferDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Bjoern PapkeLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Kathleen Klotz-NoackCharité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, 10117 Berlin, Germany.
Andrew M WatersLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Craig M GoodwinLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Prson GautamInstitute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
Mariaelena PierobonCenter for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
Sen PengDepartments of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
Thomas S K GilbertUNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Kevin H LinDepartment of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Onur DagliyanDepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Krister WennerbergInstitute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
Emanuel F PetricoinCenter for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
Nhan L TranDepartments of Cancer Biology and Neurosurgery, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
Shripad V BhagwatEli Lilly and Company, Indianapolis, IN 46285, USA.
Ramon V TiuEli Lilly and Company, Indianapolis, IN 46285, USA.
Sheng-Bin PengEli Lilly and Company, Indianapolis, IN 46285, USA.
Laura E HerringUNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Lee M GravesDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Christine SersCharité 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 WoodDepartment of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Adrienne D CoxDepartment 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 DerDepartment 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. Electronic address: cjder@med.unc.edu.
University of North Carolina at Chapel Hill · USEli Lilly (United States) · USDuke University · USGeorge Mason University · USUniversity of Helsinki · FIBerlin Institute of Health at Charité - Universitätsmedizin Berlin · DECharité - Universitätsmedizin Berlin · DEHarvard University · USMayo Clinic in Arizona · US
Funding
MEDICAL SCIENTIST TRAINING PROGRAMT32GM007171 · NIGMS · DUKE UNIVERSITY · PI KONTOS, CHRISTOPHER D · 1985 to 2021
$31.2MIntegrated Training in Cancer Model SystemsT32CA009156 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DER, CHANNING J. · 1985 to 2020
$19.7MWashington University SPORE in Pancreatic CancerP50CA196510 · NCI · WASHINGTON UNIVERSITY · PI FIELDS, RYAN C · 2016 to 2020
$10.9MProject 4: The role of codon bias in RAS tumorigenesisP01CA203657 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI GRAVES, LEE M · 2016 to 2020
$7.9MTargeting undruggable RAS for cancer treatmentR35CA232113 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DER, CHANNING J. · 2018 to 2024
$6.3MBIOLOGICAL ACTIVITY OF RAS ONCOGENESR01CA042978 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DER, CHANNING J. · 1986 to 2017
$5.9MCANCER CELL BIOLOGY TRAINING PROGRAMT32CA071341 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI CHANNING J. DER, Yuliya Pylayeva-Gupta · 1996 to 2026
$5.0MIdentification of synthetic lethal interactors in pancreatic cancerU01CA199235 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI COX, ADRIENNE D, DER, CHANNING J. · 2015 to 2019
$2.5MMechanisms of PAK1 activation, signaling and tumor resistanceR01CA175747 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DER, CHANNING J., HAHN, KLAUS M. · 2014 to 2018
$1.8MValidation of WEE1 kinase as a clinical target in KRAS-mutant pancreatic cancerF30CA243253 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DIEHL, JOHN NATHANIEL · 2019 to 2022
$180kTargeting CDK4/6 for pancreatic cancer treatmentF32CA221005 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI GOODWIN, CRAIG · 2017 to 2018
$116kNCI NIH HHS F30 CA243253NCI NIH HHS F32 CA221005NCI NIH HHS P01 CA203657NCI NIH HHS P50 CA196510NCI NIH HHS R01 CA042978NCI NIH HHS R01 CA175747NCI NIH HHS R35 CA232113NCI NIH HHS T32 CA009156NCI NIH HHS T32 CA071341NCI NIH HHS U01 CA199235NIGMS NIH HHS T32 GM007171
Abstract
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.
Indexed as
AnimalsApoptosisCarcinoma, Pancreatic DuctalCell Line, TumorHumansMAP Kinase Signaling SystemMitogen-Activated Protein Kinase KinasesMutationPancreatic NeoplasmsProtein Kinase InhibitorsProto-Oncogene Proteins c-aktProto-Oncogene Proteins p21(ras)Signal TransductionKRAS protein, humanMitogen-Activated Protein Kinase KinasesProtein Kinase InhibitorsProto-Oncogene Proteins c-aktProto-Oncogene Proteins p21(ras)ERKFOSL1KRASmesenchymal-to-epithelial transitionMYCpancreatic cancerRAF
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