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 Witkiewicz, Erik S. Knudsen, Chad V. Pecot, Naim Rashid, Peter J. Houghton, Krister Wennerberg, Adrienne D. Cox & 1 others Channing J. Der

Research output: Contribution to journalArticle

8 Citations (Scopus)

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. Vaseva et al. find that mutant KRAS regulates MYC via ERK1/2-dependent and -independent mechanisms in pancreatic cancer (PDAC). ERK1/2 blockade activates a compensatory EGFR-SRC-ERK5 cascade that stabilizes MYC, and combined ERK1/2 and ERK5 inhibition promotes synergistic loss of MYC and suppresses PDAC growth.

Original languageEnglish (US)
Pages (from-to)807-822.e7
JournalCancer Cell
Volume34
Issue number5
DOIs
StatePublished - Nov 12 2018
Externally publishedYes

Fingerprint

Adenocarcinoma
Ubiquitin-Protein Ligases
Protein Stability
Proteasome Endopeptidase Complex
Growth
Pancreatic Neoplasms
Phosphatidylinositol 3-Kinases
Proteomics
Proteolysis
Phosphorylation
Proteins

Keywords

  • EGFR
  • ERK
  • ERK5
  • FBXW7
  • KRAS
  • MYC
  • pancreatic cancer
  • PI3K
  • SRC

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Vaseva, A. V., Blake, D. R., Gilbert, T. S. K., Ng, S., Hostetter, G., Azam, S. H., ... Der, C. J. (2018). KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism. Cancer Cell, 34(5), 807-822.e7. https://doi.org/10.1016/j.ccell.2018.10.001

KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism. / Vaseva, Angelina V.; Blake, Devon R.; Gilbert, Thomas S.K.; Ng, Serina; Hostetter, Galen; Azam, Salma H.; Ozkan-Dagliyan, Irem; Gautam, Prson; Bryant, Kirsten L.; Pearce, Kenneth H.; Herring, Laura E.; Han, Haiyong; Graves, Lee M.; Witkiewicz, Agnieszka; Knudsen, Erik S.; Pecot, Chad V.; Rashid, Naim; Houghton, Peter J.; Wennerberg, Krister; Cox, Adrienne D.; Der, Channing J.

In: Cancer Cell, Vol. 34, No. 5, 12.11.2018, p. 807-822.e7.

Research output: Contribution to journalArticle

Vaseva, AV, Blake, DR, Gilbert, TSK, Ng, S, Hostetter, G, Azam, SH, Ozkan-Dagliyan, I, Gautam, P, Bryant, KL, Pearce, KH, Herring, LE, Han, H, Graves, LM, Witkiewicz, A, Knudsen, ES, Pecot, CV, Rashid, N, Houghton, PJ, Wennerberg, K, Cox, AD & Der, CJ 2018, 'KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism', Cancer Cell, vol. 34, no. 5, pp. 807-822.e7. https://doi.org/10.1016/j.ccell.2018.10.001
Vaseva AV, Blake DR, Gilbert TSK, Ng S, Hostetter G, Azam SH et al. KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism. Cancer Cell. 2018 Nov 12;34(5):807-822.e7. https://doi.org/10.1016/j.ccell.2018.10.001
Vaseva, Angelina V. ; Blake, Devon R. ; Gilbert, Thomas S.K. ; Ng, Serina ; Hostetter, Galen ; Azam, Salma H. ; Ozkan-Dagliyan, Irem ; Gautam, Prson ; Bryant, Kirsten L. ; Pearce, Kenneth H. ; Herring, Laura E. ; Han, Haiyong ; Graves, Lee M. ; Witkiewicz, Agnieszka ; Knudsen, Erik S. ; Pecot, Chad V. ; Rashid, Naim ; Houghton, Peter J. ; Wennerberg, Krister ; Cox, Adrienne D. ; Der, Channing J. / KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism. In: Cancer Cell. 2018 ; Vol. 34, No. 5. pp. 807-822.e7.
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AU - Vaseva, Angelina V.

AU - Blake, Devon R.

AU - Gilbert, Thomas S.K.

AU - Ng, Serina

AU - Hostetter, Galen

AU - Azam, Salma H.

AU - Ozkan-Dagliyan, Irem

AU - Gautam, Prson

AU - Bryant, Kirsten L.

AU - Pearce, Kenneth H.

AU - Herring, Laura E.

AU - Han, Haiyong

AU - Graves, Lee M.

AU - Witkiewicz, Agnieszka

AU - Knudsen, Erik S.

AU - Pecot, Chad V.

AU - Rashid, Naim

AU - Houghton, Peter J.

AU - Wennerberg, Krister

AU - Cox, Adrienne D.

AU - Der, Channing J.

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KW - PI3K

KW - SRC

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