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SK When we administered BRAF inhibitors to these patients, either alone or in combination with MEK inhibitors, the response rates were low—in the single digits. The reason is that after treatment with BRAF inhibitors, feedback mechanisms reactivate the endothelial growth factor receptor (EGFR), among other receptor tyrosine kinases.
BRAFi or BRAF/MEK inhibition induced cytoprotective autophagy, and autophagy inhibition enhanced BRAFi-induced cell death. Shortly after BRAF inhibitor treatment in melanoma cell lines, mutant BRAF bound the ER stress gatekeeper GRP78, which rapidly expanded the ER. Disassociation of GRP78 from the PKR-like ER-kinase (PERK) promoted a PERK-A new study has demonstrated that the phosphobinding site serine 729 mediates enhanced association between BRAF splice variants and their substrate, MEK, that is required for resistance to RAF ...