BRAF Splice Variants May Mediate Resistance to RAF Inhibitors in Patients with Melanoma

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The discovery could provide opportunities to target resistance driven by aberrantly spliced forms of BRAF V600E.
The discovery could provide opportunities to target resistance driven by aberrantly spliced forms of BRAF V600E.

A new study has demonstrated that the phosphobinding site serine 729 mediates enhanced association between BRAF splice variants and their substrate, MEK, that is required for resistance to RAF inhibitors.1

According to the researchers, whose findings were published in Cell Reports, this discovery could provide opportunities to target resistance driven by aberrantly spliced forms of BRAF V600E.

The use of US Food and Drug Administration-approved RAF inhibitors, with or without a MEK inhibitor, results in objective responses in between 50% to 70% of patients with BRAF V600E melanoma; however, many patients will eventually develop resistance.

Prior research has shown that the expression of aberrantly spliced BRAF V600E isoforms ― BRAF V600E ΔEx ― drives RAF inhibitor resistance in between 13% to 30% of patients with melanoma. This resistance occurs, in part, through enhanced dimerization.

In order to better understand the mechanisms underlying BRAF V600E ΔEx resistance, reasearchers uncoupled BRAF V600E ΔEx dimerization from maintenance of MEK-ERK1/2 signaling. Among their findings was the BRAF V600E ΔEx association with its substrate, MEK, was enhanced and required for RAF inhibitor resistance. In addition, the study showed that RAF inhibitor treatment increased phosphorylation at serine 729 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,” the researchers wrote.

In contrast, mutation of BRAF dimerization domain resulted in partial effects on MEK association and sensitivity to RAF inhibitors.

Reference

  1. Vido M, Le K, Hartsough EJ, Aplin AE. BRAF splice variant resistance to RAF inhibitor requires enhanced MEK association [published online November 6, 2018]. Cell Rep. doi: 10.1016/j.celrep.2018.10.049

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