Mechanism Of Action :
Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and reduce ligand binding to these kinases at clinically achievable concentrations (≤0.9 µM). Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression. Cetuximab is a monoclonal antibody that binds specifically to EGFR on both normal and tumor cells, competitively inhibiting binding of EGF and other ligands, such as transforming growth factor-α. Cetuximab binding blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and VEGF (vascular endothelial growth factor). Signal transduction through EGFR results in activation of wild-type KRAS protein. However, in cells with activating KRAS somatic mutations, the mutant KRAS protein is continuously active and appears to act independent of EGFR regulation. In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors. Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. Coadministration of encorafenib and cetuximab had an anti-tumor effect greater than either drug alone, in a mouse model of colorectal cancer with mutated BRAF V600E.
