| First Author | Vido MJ | Year | 2018 |
| Journal | Cell Rep | Volume | 25 |
| Issue | 6 | Pages | 1501-1510.e3 |
| PubMed ID | 30404005 | Mgi Jnum | J:351898 |
| Mgi Id | MGI:6285007 | Doi | 10.1016/j.celrep.2018.10.049 |
| Citation | Vido MJ, et al. (2018) BRAF Splice Variant Resistance to RAF Inhibitor Requires Enhanced MEK Association. Cell Rep 25(6):1501-1510.e3 |
| abstractText | Expression of aberrantly spliced BRAF V600E isoforms (BRAF V600E DeltaEx) mediates resistance in 13%-30% of melanoma patients progressing on RAF inhibitors. BRAF V600E DeltaEx confers resistance, in part, through enhanced dimerization. Here, we uncoupled BRAF V600E DeltaEx dimerization from maintenance of MEK-ERK1/2 signaling. Furthermore, we show BRAF V600E DeltaEx association with its substrate, MEK, is enhanced and required for RAF inhibitor resistance. RAF inhibitor treatment increased phosphorylation at serine 729 (S729) in BRAF V600E DeltaEx. Mutation of S729 to a non-phosphorylatable residue reduced BRAF V600E DeltaEx-MEK interaction, reduced dimerization or oligomerization, and increased RAF inhibitor sensitivity. Conversely, mutation of the BRAF dimerization domain elicited partial effects on MEK association and RAF inhibitor sensitivity. Our data implicate BRAF S729 in resistance to RAF inhibitor and underscore the importance of substrate association with BRAF V600E DeltaEx. These findings may provide opportunities to target resistance driven by aberrantly spliced forms of BRAF V600E. |
