ArticleCancer cell2018
KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism.
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Article in Cancer cell, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 120 papers.
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120citing papers in PubMed
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Who cites it
120 citing papers in PubMed, 189 citations in OpenAlex.
- MAPK-driven MYC/p21 axis controls senescence bypass and BCL-XL dependence in vincristine-resistant rhabdomyosarcoma.iScience · 2026Article
- CDK8 remodels the tumor microenvironment and promotes resistance to KRASThe EMBO journal · 2026Article
- AXL is a novel ERK5/KLF4 target in MEK inhibitor-treated melanoma.Neoplasia (New York, N.Y.) · 2026Article
- KRAS and MYC synergistic inhibition: a powerful strategy targeting KRAS-mutant cancers.Molecular cancer · 2026Review
- Dose-Dependent Inhibition of Protein Glycosylation Reveals Crosstalk between Glycosylation and Phosphorylation in EGF Signaling Pathways.Analytical chemistry · 2026Article
- MAPK ERK5 is a novel regulator of MHC-I in cancer cells.Cell communication and signaling : CCS · 2026Article
- Rationally and in silico guided APOBEC3F-directed CBE for enhanced PDAC genetic therapy.Communications biology · 2026Article
- Article
- c-Myc/GRPEL1 maintains fatty acid synthesis via FASN to support PDAC cell proliferation.Cell death & disease · 2026Article
- Development of a chaperone-mediated protein degrader targeting ERK5 that efficaciously reduces tumor growth.Cell communication and signaling : CCS · 2026Article
- HDAC5 deficiency induces intrinsic resistance to KRAS inhibition by disrupting c-Myc acetylation-ubiquitination homeostasis.The Journal of clinical investigation · 2026Article
- Pancreatic cancer: molecular pathogenesis and emerging therapeutic strategies.Signal transduction and targeted therapy · 2026Review
- USP10-mediated deubiquitination and activation ofActa pharmaceutica Sinica. B · 2026Article
- MEK5/ERK5 inhibition sensitizes NRAS-mutant melanoma to MAPK-targeted therapy by preventing Cyclin D/CDK4-mediated G1/S progression.Cell death & disease · 2025Article
- Inverted chimeric RNAi molecules synergistically cotarget MYC and KRAS in KRAS-driven cancers.The Journal of clinical investigation · 2025Article
- Defining the MYC-regulated transcriptome and kinome that support KRAS- and ERK-dependent growth of pancreatic cancer.Science signaling · 2025Article
- PRMT5 Inhibition as a Potential Strategy for KRAS Mutant CRC: Downstream Mediators of the PRMT5-KRAS Crosstalk.Current issues in molecular biology · 2025Article
- KRAS: the Achilles' heel of pancreas cancer biology.The Journal of clinical investigation · 2025Review
- Low-amplitude copy number gains shape cancer through known and novel oncogenes with associated therapeutic vulnerabilities.Nucleic acids research · 2025Article
- Proteomics in pancreatic cancer.Biomarker research · 2025Review
60 more citing papers are in PubMed but not listed here.
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Authors and funding
21 authors at 6 institutions in 2 countries.
Angelina V VasevaLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; The Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Devon R BlakeDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Thomas S K GilbertDepartment 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.
Serina NgDepartment of Molecular and Cellular Biology, Roswell Park Cancer Center, Buffalo, NY 14203, USA.
Galen HostetterPathology and Biorepository Core, The Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Salma H AzamCurriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Irem Ozkan-DagliyanDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Prson GautamInstitute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
Kirsten L BryantLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Kenneth H PearceCenter for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Laura E HerringDepartment 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.
Haiyong HanMolecular Medicine Division, Translational Genomic Research Institute, Phoenix, AZ 85004, USA.
Lee M GravesLineberger 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.
Agnieszka K WitkiewiczCenter for Personalized Medicine, Roswell Park Cancer Center, Buffalo, NY 14203, USA.
Erik S KnudsenDepartment of Molecular and Cellular Biology, Roswell Park Cancer Center, Buffalo, NY 14203, USA.
Chad V PecotLineberger Comprehensive Cancer Center, 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; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Naim RashidLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Peter J HoughtonThe Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Krister WennerbergInstitute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
Adrienne D CoxLineberger 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; Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Channing J DerLineberger 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. Electronic address: cjder@med.unc.edu.
University of North Carolina at Chapel Hill · USRoswell Park Comprehensive Cancer Center · USInstitute for Molecular Medicine Finland · FIThe University of Texas Health Science Center at San Antonio · USTranslational Genomics Research Institute · USVan Andel Institute · US
Funding
Virology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Deborah F. Tate · 1985 to 2026
$201.5MIntegrated 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 COUNTER, CHRISTOPHER 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
$2.5MBreaking the paradigm: RhoA as a tumor suppressor in cancerF31CA216965 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI BLAKE, DEVON R · 2017 to 2018
$57kNCI NIH HHS F31 CA216965NCI NIH HHS P01 CA203657NCI NIH HHS P30 CA016086NCI NIH HHS P50 CA196510NCI NIH HHS R01 CA042978NCI NIH HHS R35 CA232113NCI NIH HHS T32 CA009156NCI NIH HHS T32 CA071341NCI NIH HHS U01 CA199235
Abstract
Our recent ERK1/2 inhibitor analyses in pancreatic ductal adenocarcinoma (PDAC) indicated ERK1/2-independent mechanisms maintaining MYC protein stability. To identify these mechanisms, we determined the signaling networks by which mutant KRAS regulates MYC. Acute KRAS suppression caused rapid proteasome-dependent loss of MYC protein, through both ERK1/2-dependent and -independent mechanisms. Surprisingly, MYC degradation was independent of PI3K-AKT-GSK3β signaling and the E3 ligase FBWX7. We then established and applied a high-throughput screen for MYC protein degradation and performed a kinome-wide proteomics screen. We identified an ERK1/2-inhibition-induced feedforward mechanism dependent on EGFR and SRC, leading to ERK5 activation and phosphorylation of MYC at S62, preventing degradation. Concurrent inhibition of ERK1/2 and ERK5 disrupted this mechanism, synergistically causing loss of MYC and suppressing PDAC growth.
Indexed as
AnimalsCarcinoma, Pancreatic DuctalCell Line, TumorErbB ReceptorsGlycogen Synthase Kinase 3 betaHumansMAP Kinase Kinase 5MiceMice, Inbred NODMice, KnockoutMice, SCIDMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Mitogen-Activated Protein Kinase 7Pancreatic NeoplasmsPhosphatidylinositol 3-KinasesEGFR protein, humanErbB ReceptorsGlycogen Synthase Kinase 3 betaGSK3B protein, humanMAP2K5 protein, humanMAPK1 protein, humanMAPK3 protein, humanMAPK7 protein, humanMAP Kinase Kinase 5Mitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Mitogen-Activated Protein Kinase 7MYC protein, humanPhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-mycProto-Oncogene Proteins p21(ras)src-Family KinasesEGFRERKERK5FBXW7KRASMYCpancreatic cancerPI3KSRC
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