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

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. CoxChanning J. Der

Research output: Contribution to journal › Article › peer-review

101 Scopus citations

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 language	English (US)
Pages (from-to)	807-822.e7
Journal	Cancer Cell
Volume	34
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2018.10.001
State	Published - Nov 12 2018
Externally published	Yes

Keywords

EGFR
ERK
ERK5
FBXW7
KRAS
MYC
PI3K
SRC
pancreatic cancer

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2018.10.001

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Vaseva, A. V., Blake, D. R., Gilbert, T. S. K., Ng, S., Hostetter, G., Azam, S. H., Ozkan-Dagliyan, I., Gautam, P., Bryant, K. L., Pearce, K. H., Herring, L. E., Han, H., Graves, L. M., Witkiewicz, A. K., Knudsen, E. S., Pecot, C. V., Rashid, N., Houghton, P. J., Wennerberg, K., ... 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

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, AK, 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

@article{a13ca74051a84886ba447ea17781981b,

title = "KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism",

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.",

keywords = "EGFR, ERK, ERK5, FBXW7, KRAS, MYC, PI3K, SRC, pancreatic cancer",

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

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = nov,

day = "12",

doi = "10.1016/j.ccell.2018.10.001",

language = "English (US)",

volume = "34",

pages = "807--822.e7",

journal = "Cancer Cell",

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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.

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.

KW - EGFR

KW - ERK

KW - ERK5

KW - FBXW7

KW - KRAS

KW - MYC

KW - PI3K

KW - SRC

KW - pancreatic cancer

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U2 - 10.1016/j.ccell.2018.10.001

DO - 10.1016/j.ccell.2018.10.001

M3 - Article

C2 - 30423298

AN - SCOPUS:85055025498

SN - 1535-6108

VL - 34

SP - 807-822.e7

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

Abstract

Keywords

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