title: Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression.
abstract: Induction of compensatory mechanisms and ERK reactivation has limited the effectiveness of Raf and MEK inhibitors in RAS-mutant cancers. We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase (PI3K) inhibition caused synergistic cell death. Additional combinations that enhanced ERK inhibitor action were also identified. Unexpectedly, long-term treatment of sensitive cell lines caused senescence, mediated in part by MYC degradation and p16 reactivation. Enhanced basal PI3K-AKT-mTOR signaling was associated with de novo resistance to ERK inhibitor, as were other protein kinases identified by kinome-wide siRNA screening and a genetic gain-of-function screen. Our findings reveal distinct consequences of inhibiting this kinase cascade at the level of ERK.
authors.affiliation: 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.
authors.forename: Tikvah K
authors.initials: TK
authors.lastname: Hayes
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Neel
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chaoxin
authors.initials: C
authors.lastname: Hu
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Prson
authors.initials: P
authors.lastname: Gautam
authors.affiliation: Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Chenard
authors.affiliation: Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Long
authors.affiliation: Departments of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
authors.forename: Meraj
authors.initials: M
authors.lastname: Aziz
authors.affiliation: Departments of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kassner
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: Bryant
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
authors.forename: Mariaelena
authors.initials: M
authors.lastname: Pierobon
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Raoud
authors.initials: R
authors.lastname: Marayati
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Swapnil
authors.initials: S
authors.lastname: Kher
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: George
authors.affiliation: Divisions of Oncology, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA; Division of Medical Oncology, Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: Mai
authors.initials: M
authors.lastname: Xu
authors.affiliation: Divisions of Oncology, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA; Division of Medical Oncology, Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.affiliation: Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Samatar
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Krister
authors.initials: K
authors.lastname: Wennerberg
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.affiliation: Departments of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
authors.forename: Hongwei H
authors.initials: HH
authors.lastname: Yin
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Nelkin
authors.affiliation: 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; Department of Pharmacology, 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.
authors.forename: Adrienne D
authors.initials: AD
authors.lastname: Cox
authors.affiliation: 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; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jen Jen
authors.initials: JJ
authors.lastname: Yeh
authors.affiliation: 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; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: cjder@med.unc.edu.
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Der
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D013995:Time
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D016283:Proto-Oncogene Proteins p21(ras); C489428:Myc protein, mouse; C495971:Hras protein, mouse