AI Article Synopsis
- * Through various tests, we found that combining RAFi with ERK inhibitors (ERKi) produces strong anti-tumor effects at low doses, while using them individually only slows cancer cell growth.
- * Detailed studies reveal that this combination disrupts cancer cell signaling pathways and promotes a transition that makes cells less aggressive, indicating it could be a promising treatment approach for this type of cancer.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393480 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2020.107764 | DOI Listing |
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