Melanomas carrying a mutant BRAF gene generally respond to treatment with BRAF inhibitors, but in the majority of cases resistant cancer clones emerge. It has been shown that such resistant clones can nevertheless exhibit reduced fitness when the drug is removed. This paper demonstrates a molecular mechanism underlying this observation. Rene Bernards and colleagues show that a signalling cascade leading from suppression of SOX10 to increased expression of the EGFR (epidermal growth factor receptor) gene confers resistance to BRAF inhibitors and at the same time reduces melanoma cell proliferation and induces senescence in the absence of inhibitors.
With preliminary evidence that this pathway is induced in patients who have developed resistance, the authors suggest that temporary withdrawal of BRAF inhibitors — a drug holiday — would reverse induced EGFR expression and thus may re-sensitize melanoma cells to BRAF inhibition when treatment is reinstated.