Research ArticleCancer

Gatekeeper Mutations Mediate Resistance to BRAF-Targeted Therapies

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Science Translational Medicine  09 Jun 2010:
Vol. 2, Issue 35, pp. 35ra41
DOI: 10.1126/scitranslmed.3000758

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Getting Back on Target

The identification of clinically useful small-molecule inhibitors of dysregulated proteins that trigger a cascade of detrimental downstream effects during the process of tumorigenesis requires a highly precise understanding of the specific residues responsible for the damage. However, although this information can elucidate promising candidate targets, clinical data have revealed that the utility of anticancer drugs within tumors of similar origin and mutational status is variable. It has been postulated that the haphazard effects of such drugs are the result of off-targeting effects—that is, the ability of a drug to inhibit tumor growth in a manner less specific than that which it was optimally designed for. In an era that now seeks to further personalize medicine, these off-targeting effects reveal how distant we remain from truly achieving an individualized cancer cocktail.

In melanoma, the failure of the FDA-approved drug sorafenib to consistently curb disease in individuals with tumors that harbor cancer-driving mutations in BRAF—the overactive kinase presumed to be the target of the drug on the basis of its efficacy against CRAF—raised doubts as to the utility of BRAF as true melanoma target, despite its more successful application as a liver and kidney cancer therapeutic. Now, Marais and colleagues have designed a system by which to tease apart whether BRAF-mediated therapeutics such as sorafenib and PLX4720 inhibit tumor growth by homing in on the gatekeeper mutations that cause aberrant signaling in BRAF or by other nonspecific tumor-inhibiting mechanisms. Their compelling results reveal that BRAF is indeed a tractable target for melanoma, and while a plethora of tractable cancer targets are continuously being resolved, the need for proper preclinical validation—where the effects can easily be discerned as being mechanistic or off-target—is paramount to developing the right drug for the specific target.


  • Citation: S. Whittaker, R. Kirk, R. Hayward, A. Zambon, A. Viros, N. Cantarino, A. Affolter, A. Nourry, D. Niculescu-Duvaz, C. Springer, R. Marais, Gatekeeper mutations mediate resistance to BRAF-targeted therapies. Sci. Transl. Med. 2, 35ra41 (2010).

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