2. Academic Validation
  3. KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism

KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism

  • Cancer Cell. 2018 Nov 12;34(5):807-822.e7. doi: 10.1016/j.ccell.2018.10.001.
Angelina V Vaseva 1,  Devon R Blake 2,  Thomas S K Gilbert 3,  Serina Ng 4,  Galen Hostetter 5,  Salma H Azam 6,  Irem Ozkan-Dagliyan 2,  Prson Gautam 7,  Kirsten L Bryant 8,  Kenneth H Pearce 9,  Laura E Herring 3,  Haiyong Han 10,  Lee M Graves 11,  Agnieszka K Witkiewicz 12,  Erik S Knudsen 4,  Chad V Pecot 13,  Naim Rashid 14,  Peter J Houghton 15,  Krister Wennerberg 7,  Adrienne D Cox 16,  Channing J Der 17
Affiliations

Affiliations

  • 1 Lineberger 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.
  • 2 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3 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.
  • 4 Department of Molecular and Cellular Biology, Roswell Park Cancer Center, Buffalo, NY 14203, USA.
  • 5 Pathology and Biorepository Core, The Van Andel Research Institute, Grand Rapids, MI 49503, USA.
  • 6 Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 7 Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
  • 8 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 9 Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 10 Molecular Medicine Division, Translational Genomic Research Institute, Phoenix, AZ 85004, USA.
  • 11 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.
  • 12 Center for Personalized Medicine, Roswell Park Cancer Center, Buffalo, NY 14203, USA.
  • 13 Lineberger 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.
  • 14 Lineberger 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.
  • 15 The Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • 16 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; Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 17 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. Electronic address: cjder@med.unc.edu.
PMID: 30423298 DOI: 10.1016/j.ccell.2018.10.001
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.

Keywords

EGFR; ERK; ERK5; FBXW7; KRAS; MYC; PI3K; SRC; pancreatic cancer.

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