Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers

Irem Ozkan-Dagliyan, J. Nathaniel Diehl, Samuel D. George, Antje Schaefer, Bjoern Papke, Kathleen Klotz-Noack, Andrew M. Waters, Craig M. Goodwin, Prson Gautam, Mariaelena Pierobon, Sen Peng, Thomas S.K. Gilbert, Kevin H. Lin, Onur Dagliyan, Krister Wennerberg, Emanuel F. Petricoin, Nhan L. Tran, Shripad V. Bhagwat, Ramon V. Tiu, Sheng Bin PengLaura E. Herring, Lee M. Graves, Christine Sers, Kris C. Wood, Adrienne D. Cox, Channing J. Der*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF (RAFi) and ERK (ERKi), is highly synergistic at low doses in cell line, organoid, and rat models of PDAC, whereas each inhibitor alone is only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA) pathway mapping and RNA sequencing (RNA-seq) show that RAFi/ERKi induced insensitivity to loss of negative feedback and system failures including loss of ERK signaling, FOSL1, and MYC; shutdown of the MYC transcriptome; and induction of mesenchymal-to-epithelial transition. We conclude that low-dose vertical inhibition of the RAF-MEK-ERK cascade is an effective therapeutic strategy for KRAS mutant PDAC.

Original languageEnglish
Article number107764
JournalCell Reports
Volume31
Issue number11
DOIs
StatePublished - 16 Jun 2020
Externally publishedYes

Keywords

  • ERK
  • FOSL1
  • KRAS
  • MYC
  • RAF
  • mesenchymal-to-epithelial transition
  • pancreatic cancer

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