@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 = "Funding Information: We thank Eric Collisson (University of California, San Francisco) for the INK4.1syn_Luc cell line, Kris Wood (Duke) for the Cancer Toolkit expression vectors, Michael Emanuele (University of North Carolina at Chapel Hill) for the pGPS-LP plasmid, and Edward Favors and Abhik Bandyopadhyay for technical assistance (The Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio). Support was provided by grants from the National Cancer Institute (NCI) (CA199235 and CA203657) to C.J.D. and A.D.C., and from the NCI (CA42978, CA196510), the Pancreatic Cancer Action Network/AACR, Department of Defense, and the Lustgarten Pancreatic Cancer Foundation to C.J.D. A.V.V. was supported by fellowships from the NCI (T32CA009156) and American Cancer Society (128014-PF-15-059-01-TBE). D.R.B. was supported by NCI fellowships (T32CA071341 and F31CA216965), I.O.D. by the Slomo and Cindy Silvian Foundation and K.L.B. was supported by T32CA009156 and a grant from the Pancreatic Cancer Action Network/AACR. This research is based in part upon work conducted using the UNC Proteomics Core Facility, which is supported in part by the P30 CA016086 Cancer Center Core Support Grant to UNC. Funding Information: We thank Eric Collisson (University of California, San Francisco) for the INK4.1 syn_Luc cell line, Kris Wood (Duke) for the Cancer Toolkit expression vectors, Michael Emanuele (University of North Carolina at Chapel Hill) for the pGPS-LP plasmid, and Edward Favors and Abhik Bandyopadhyay for technical assistance (The Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio). Support was provided by grants from the National Cancer Institute (NCI) ( CA199235 and CA203657 ) to C.J.D. and A.D.C., and from the NCI ( CA42978 , CA196510 ), the Pancreatic Cancer Action Network / AACR , Department of Defense , and the Lustgarten Pancreatic Cancer Foundation to C.J.D. A.V.V. was supported by fellowships from the NCI ( T32CA009156 ) and American Cancer Society ( 128014-PF-15-059-01-TBE ). D.R.B. was supported by NCI fellowships ( T32CA071341 and F31CA216965 ), I.O.D. by the Slomo and Cindy Silvian Foundation and K.L.B. was supported by T32CA009156 and a grant from the Pancreatic Cancer Action Network/AACR. This research is based in part upon work conducted using the UNC Proteomics Core Facility, which is supported in part by the P30 CA016086 Cancer Center Core Support Grant to UNC. 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",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",
}