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

Angelina V Vaseva; Devon R Blake; Thomas S K Gilbert; Serina Ng; Galen Hostetter; Salma H Azam; Irem Ozkan-Dagliyan; Prson Gautam; Kirsten L Bryant; Kenneth H Pearce; Laura E Herring; Haiyong Han; Lee M Graves; Agnieszka K Witkiewicz; Erik S Knudsen; Chad V Pecot; Naim Rashid; Peter J Houghton; Krister Wennerberg; Adrienne D Cox; Channing J Der

doi:10.1016/j.ccell.2018.10.001

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.

Authors

Angelina V Vaseva¹, Devon R Blake², Thomas S K Gilbert³, Serina Ng⁴, Galen Hostetter⁵, Salma H Azam⁶, Irem Ozkan-Dagliyan², Prson Gautam⁷, Kirsten L Bryant⁸, Kenneth H Pearce⁹, Laura E Herring³, Haiyong Han¹⁰, Lee M Graves¹¹, Agnieszka K Witkiewicz¹², Erik S Knudsen⁴, Chad V Pecot¹³, Naim Rashid¹⁴, Peter J Houghton¹⁵, Krister Wennerberg⁷, Adrienne D Cox¹⁶, Channing J Der¹⁷

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / pathology*
Cell Line, Tumor
ErbB Receptors / metabolism
Glycogen Synthase Kinase 3 beta / metabolism
Humans
MAP Kinase Kinase 5 / metabolism*
Mice
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Mitogen-Activated Protein Kinase 1 / metabolism*
Mitogen-Activated Protein Kinase 3 / metabolism*
Mitogen-Activated Protein Kinase 7 / metabolism*
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / pathology*
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-myc / metabolism*
Proto-Oncogene Proteins p21(ras) / genetics*
src-Family Kinases / metabolism

Substances

MYC protein, human
Proto-Oncogene Proteins c-myc
Phosphatidylinositol 3-Kinases
EGFR protein, human
ErbB Receptors
src-Family Kinases
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Proto-Oncogene Proteins c-akt
MAPK1 protein, human
MAPK3 protein, human
MAPK7 protein, human
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 7
MAP Kinase Kinase 5
MAP2K5 protein, human
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding