RAF kinase inhibitors such as vemurafenib are clinically app...
| created | [InstanceEdit:6802233] Rothfels, Karen, 2015-10-02 |
| dbId | 6802234 |
| displayName | RAF kinase inhibitors such as vemurafenib are clinically app... |
| modified | [InstanceEdit:6804145] Rothfels, Karen, 2015-10-08 |
| schemaClass | Summation |
| text |
RAF kinase inhibitors such as vemurafenib are clinically approved for treatment of BRAF-driven melanomas. Despite initial positive response to drug treatment, however, many tumors go on to develop resistance to the RAF inhibitors (Flaherty et al, 2010; Chapman et al, 2011; Sosman et al, 2012; Solit et al, 2011; reviewed in Lito et al, 2013). One mechanism that contributes to acquired resistance to RAF inhibitors is the expression of a splice variant of V600E that lacks the N-terminal RAS-binding domain. This variant displays increased RAS-independent dimerization and increased signaling relative to the full-length V600E, consistent with the notion that it is the monomeric form of BRAF that is sensitive to inhibition. Disruption of the dimer interface in this p61-V600E splice variant restores sensitivity to inhibition (Poulikakos et al, 2011; reviewed in Lito et al, 2013). Other mechanisms of BRAF inhibitor resistance include mutational activation of NRAS or receptor tyrosine kinases, inactivation of the GAP protein NF1, or increased expression of RAF1 or BRAF (Nazarian et al, 2010; Maertens et al, 2013; Whittaker et al, 2013; Shi et al, 2012; Montagut et al, 2008; reviewed in Chapman, 2013; Lito et al, 2013). |
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