Application of a MYC degradation screen identifies sensitivity to CDK9 inhibitors in KRAS-mutant pancreatic cancer

Devon R. Blake, Angelina V. Vaseva, Richard G. Hodge, McKenzie P. Kline, Thomas S.K. Gilbert, Vikas Tyagi, Daowei Huang, Gabrielle C. Whiten, Jacob E. Larson, Xiaodong Wang, Kenneth H. Pearce, Laura E. Herring, Lee M. Graves, Stephen V. Frye, Michael J. Emanuele, Adrienne D. Cox, Channing J. Der

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Stabilization of the MYC oncoprotein by KRAS signaling critically promotes the growth of pancreatic ductal adenocarcinoma (PDAC). Thus, understanding how MYC protein stability is regulated may lead to effective therapies. Here, we used a previously developed, flow cytometry-based assay that screened a library of >800 protein kinase inhibitors and identified compounds that promoted either the stability or degradation of MYC in a KRAS-mutant PDAC cell line. We validated compounds that stabilized or destabilized MYC and then focused on one compound, UNC10112785, that induced the substantial loss of MYC protein in both two-dimensional (2D) and 3D cell cultures. We determined that this compound is a potent CDK9 inhibitor with a previously uncharacterized scaffold, caused MYC loss through both transcriptional and posttranslational mechanisms, and suppresses PDAC anchorage-dependent and anchorage-independent growth. We discovered that CDK9 enhanced MYC protein stability through a previously unknown, KRAS-independent mechanism involving direct phosphorylation of MYC at Ser62. Our study thus not only identifies a potential therapeutic target for patients with KRAS-mutant PDAC but also presents the application of a screening strategy that can be more broadly adapted to identify regulators of protein stability.

Original languageEnglish (US)
Article numberY
JournalScience signaling
Volume12
Issue number590
DOIs
StatePublished - Jul 16 2019
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Blake, D. R., Vaseva, A. V., Hodge, R. G., Kline, M. P., Gilbert, T. S. K., Tyagi, V., Huang, D., Whiten, G. C., Larson, J. E., Wang, X., Pearce, K. H., Herring, L. E., Graves, L. M., Frye, S. V., Emanuele, M. J., Cox, A. D., & Der, C. J. (2019). Application of a MYC degradation screen identifies sensitivity to CDK9 inhibitors in KRAS-mutant pancreatic cancer. Science signaling, 12(590), [Y]. https://doi.org/10.1126/scisignal.aav7259