2. Academic Validation
  3. Application of a MYC degradation screen identifies sensitivity to CDK9 inhibitors in KRAS-mutant pancreatic cancer

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

  • Sci Signal. 2019 Jul 16;12(590):eaav7259. doi: 10.1126/scisignal.aav7259.
Devon R Blake 1,  Angelina V Vaseva 2,  Richard G Hodge 2,  McKenzie P Kline 3,  Thomas S K Gilbert 1 4,  Vikas Tyagi 5,  Daowei Huang 5,  Gabrielle C Whiten 5,  Jacob E Larson 5,  Xiaodong Wang 2 5,  Kenneth H Pearce 5,  Laura E Herring 1 4,  Lee M Graves 1 2 4,  Stephen V Frye 2 5,  Michael J Emanuele 1 2,  Adrienne D Cox 1 2 6,  Channing J Der 7 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3 Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 4 UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 5 Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 6 Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 7 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. cjder@med.unc.edu.
PMID: 31311847 DOI: 10.1126/scisignal.aav7259
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.

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