Journal
CANCER CELL
Volume 34, Issue 5, Pages 807-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.10.001
Keywords
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Funding
- National Cancer Institute (NCI) [CA199235, CA203657]
- NCI [T32CA009156, CA42978, CA196510, T32CA071341, F31CA216965]
- Pancreatic Cancer Action Network/AACR
- Lustgarten Pancreatic Cancer Foundation
- American Cancer Society [128014-PF-15-059-01-TBE]
- Slomo and Cindy Silvian Foundation
- Cancer Center Core Support Grant [P30 CA016086]
- Department of Defense
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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-GSK36 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.
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