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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Ozkan-Dagliyan, I; Diehl, JN; George, SD; Schaefer, A; Papke, B; Klotz-Noack, K; Waters, AM; Goodwin, CM; Gautam, P; Pierobon, M; Peng, S; Gilbert, TSK; Lin, KH; Dagliyan, O; Wennerberg, K; Petricoin, EF; Tran, NL; Bhagwat, SV; Tiu, RV; Peng, S-B; Herring, LE; Graves, LM; Sers, C; Wood, KC; Cox, AD; Der, CJ

Published Date

  • June 16, 2020

Published In

Volume / Issue

  • 31 / 11

Start / End Page

  • 107764 -

PubMed ID

  • 32553168

Pubmed Central ID

  • 32553168

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2020.107764

Language

  • eng

Conference Location

  • United States