LOW-DOSE Vertical Inhibition Of The RAF-MEK-ERK Cascade Causes Apoptotic Death Of KRAS Mutant Cancers
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, 3rd, Tran NL, Bhagwat SV, Tiu RV, Peng SB, Herring LE, Graves LM, Sers C, Wood KC, Cox AD and Der CJ.
Cell Rep. 2020 Jun 16;31(11):107764
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.