A melanoma patient with a B-RAF(V600E)
tumour initially responds well to the BRAF inhibitor vemurafenib, but the
tumour later resumes rapid growth. Genetic analysis reveals the presence of a
p61 B-RAF(V600E) splice variant that lacks part of the regulatory region of the
protein.

Which mechanism best explains why this
variant confers resistance to vemurafenib?

Question

A melanoma patient with a B-RAF(V600E)
tumour initially responds well to the BRAF inhibitor vemurafenib, but the
tumour later resumes rapid growth. Genetic analysis reveals the presence of a
p61 B-RAF(V600E) splice variant that lacks part of the regulatory region of the
protein.

Which mechanism best explains why this
variant confers resistance to vemurafenib?

Accepted Answer

The
truncated p61 BRAF protein forms active dimers, maintaining strong MEK
signalling despite inhibitor treatment

Answer

Loss of the
regulatory region causes constitutive RAS activation, which bypasses BRAF
inhibition and activates MEK

Answer

The truncated p61 BRAF
variant enhances binding to MEK, allowing MEK to remain phosphorylated even
when BRAF catalytic activity is inhibited

Answer

The splice variant
increases BRAF protein stability, resulting in higher cellular levels that
overwhelm the inhibitor

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A melanoma patient with a B-RAF(V600E) tumour initially responds well to the BR...

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