The mechanism of drug resistance in BRAF (V600E) mutant melanoma


Drugs that inhibit the activities of BRAF or MEK kinases are always effective for patients with BRAF (V600E) mutant melanoma, however, resistance develops inevitable. Some evidences of colon cancers with the same BRAF (V600E) mutation shows that the resistance may be related to epidermal growth factor receptor (EGFR) feedback activation. Sun et al. demonstrated the resistance of BRAF (V600E) , involves several transduction factors, is reversible and adaptive. The letter was published on Nature.


Researchers found an increased EGFR expression level after the resistance to BRAF or MEK inhibitors emerged. By looking into the mechanism of drug resistance, they found the elevation of EGFR and platelet-derived growth factor receptor-β (PDGFRB) levels are due to activation of TGF-β signaling, triggered by the suppression of sex determining region Y-box 10 (SOX10). Furthermore, drug resistance showed by melanoma cells with low SOX10 and consequently high EGFR expression levels were reversed when drug treatment was interrupted, indicating the adaptive response is not effective in the absence of drug. The finding revealed the mechanism of clinical evidence that patients who have developed drug resistance can retrieve sensitivity after "drug holiday".


Nature. 2014 Apr 3;508(7494):118-22.

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