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

40 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 language	English
Journal	Cancer Cell
Volume	34
Issue number	5
Pages (from-to)	807-822.e1-e7
Number of pages	23
ISSN	1535-6108
DOIs	https://doi.org/10.1016/j.ccell.2018.10.001
Publication status	Published - 12 Nov 2018
Externally published	Yes

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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.e1-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.e1-e7. https://doi.org/10.1016/j.ccell.2018.10.001

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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.",

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}",

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

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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.

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 -

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

Abstract

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