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
  • 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: [email protected].
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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