BRAF 剪接变异体对 RAF 抑制剂的耐药性需要增强的 MEK 结合。
BRAF Splice Variant Resistance to RAF Inhibitor Requires Enhanced MEK Association.
机构信息
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Jefferson College of Biomedical Sciences, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
出版信息
Cell Rep. 2018 Nov 6;25(6):1501-1510.e3. doi: 10.1016/j.celrep.2018.10.049.
Expression of aberrantly spliced BRAF V600E isoforms (BRAF V600E ΔEx) mediates resistance in 13%-30% of melanoma patients progressing on RAF inhibitors. BRAF V600E ΔEx confers resistance, in part, through enhanced dimerization. Here, we uncoupled BRAF V600E ΔEx dimerization from maintenance of MEK-ERK1/2 signaling. Furthermore, we show BRAF V600E ΔEx 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 ΔEx. Mutation of S729 to a non-phosphorylatable residue reduced BRAF V600E ΔEx-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 ΔEx. These findings may provide opportunities to target resistance driven by aberrantly spliced forms of BRAF V600E.
异常剪接的 BRAF V600E 异构体（BRAF V600E ΔEx）的表达介导了 13%-30%的黑色素瘤患者对 RAF 抑制剂进展的耐药性。BRAF V600E ΔEx 通过增强二聚化来介导耐药性。在这里，我们将 BRAF V600E ΔEx 的二聚化与 MEK-ERK1/2 信号的维持解耦。此外，我们表明 BRAF V600E ΔEx 与它的底物 MEK 的结合增强，并需要 RAF 抑制剂的耐药性。 RAF 抑制剂治疗增加了 BRAF V600E ΔEx 中丝氨酸 729（S729）的磷酸化。将 S729 突变为非磷酸化残基可降低 BRAF V600E ΔEx-MEK 相互作用，降低二聚化或寡聚化，并增加 RAF 抑制剂的敏感性。相反，BRAF 二聚化结构域的突变对 MEK 结合和 RAF 抑制剂敏感性产生部分影响。我们的数据表明 BRAF S729 参与 RAF 抑制剂的耐药性，并强调了底物与 BRAF V600E ΔEx 结合的重要性。这些发现可能为靶向由 BRAF V600E 异常剪接形式驱动的耐药性提供机会。
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