| Literature DB >> 30423298 |
Angelina V Vaseva1, Devon R Blake2, Thomas S K Gilbert3, Serina Ng4, Galen Hostetter5, Salma H Azam6, Irem Ozkan-Dagliyan2, Prson Gautam7, Kirsten L Bryant8, Kenneth H Pearce9, Laura E Herring3, Haiyong Han10, Lee M Graves11, Agnieszka K Witkiewicz12, Erik S Knudsen4, Chad V Pecot13, Naim Rashid14, Peter J Houghton15, Krister Wennerberg7, Adrienne D Cox16, Channing J Der17.
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.Entities:
Keywords: EGFR; ERK; ERK5; FBXW7; KRAS; MYC; PI3K; SRC; pancreatic cancer
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Year: 2018 PMID： 30423298 PMCID： PMC6321749 DOI： 10.1016/j.ccell.2018.10.001
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743