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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • 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
  • Adrienne D Cox
  • Channing J Der

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.

TidsskriftCancer Cell
Udgave nummer5
Sider (fra-til)807-822.e1-e7
Antal sider23
StatusUdgivet - 2018
Eksternt udgivetJa

Bibliografisk note

Copyright © 2018 Elsevier Inc. All rights reserved.

ID: 215091591