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

TY - JOUR

T1 - KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism

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 K

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

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/11/12

Y1 - 2018/11/12

N2 - 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.

AB - 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.

U2 - 10.1016/j.ccell.2018.10.001

DO - 10.1016/j.ccell.2018.10.001

M3 - Journal article

C2 - 30423298

SN - 1535-6108

VL - 34

SP - 807-822.e1-e7

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -