Journal article
BRAF Splice Variant Resistance to RAF Inhibitor Requires Enhanced MEK Association
Cell reports (Cambridge), v 25(6), pp 1501-1510.e3
06 Nov 2018
PMID: 30404005
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Expression of aberrantly spliced BRAF V600E isoforms (BRAF V600E Delta Ex) mediates resistance in 13%-30% of melanoma patients progressing on RAF inhibitors. BRAF V600E Delta Ex confers resistance, in part, through enhanced dimerization. Here, we uncoupled BRAF V600E Delta Ex dimerization from maintenance of MEK-ERK1/2 signaling. Furthermore, we show BRAF V600E Delta Ex 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 Delta Ex. Mutation of S729 to a non-phosphorylatable residue reduced BRAF V600E Delta Ex-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 Delta Ex. These findings may provide opportunities to target resistance driven by aberrantly spliced forms of BRAF V600E.
Metrics
Details
- Title
- BRAF Splice Variant Resistance to RAF Inhibitor Requires Enhanced MEK Association
- Creators
- Michael J. Vido - Thomas Jefferson UniversityKaitlyn Le - Thomas Jefferson UniversityEdward J. Hartsough - Thomas Jefferson UniversityAndrew E. Aplin - Thomas Jefferson University
- Publication Details
- Cell reports (Cambridge), v 25(6), pp 1501-1510.e3
- Publisher
- Elsevier
- Number of pages
- 13
- Grant note
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation P30-CA56036 / NCI Support Grant F30-CA203314; K99-CA207855; R01-CA182635 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R00CA207855 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000449476500011
- Scopus ID
- 2-s2.0-85055748522
- Other Identifier
- 991020531936704721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Cell Biology