Concurrent RAF+ERK inhibition induces mesenchymal-to-epithelial transition, silences the MYC-dependent transcriptome

We addressed whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identified combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF and ERK (ERKi), was highly synergistic at low doses in cell line, organoid and mouse models of PDAC, whereas eachinhibitor alone was only cytostatic. Comprehensive mechanistic signaling studies, using reverse phase protein array (RPPA) pathway mapping and RNA-Seq, showed 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 KRASmutant PDAC.