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Answer found for cancer drug failure

A recently approved cancer drug that was hailed as a miracle worker for some patients with advanced melanoma has mysteriously failed in early clinical trials against colon cancers. But work published today in Nature clarifies how colon cancers dodge the drug, called vemurafenib, and what can be done to overcome this resistance.

Vemurafenib (once known as PLX4032) was approved last year for the treatment of advanced melanomas that bear a mutation in a protein called BRAF  (see ‘Melanoma drug gets speedy approval’). Its dramatic — although admittedly short-lived (see ‘The roots of resistance‘) — success against melanoma raised hopes that the drug could be used against other cancers that harbor the same mutation (see ‘Rare victory in fight against melanoma’ and ‘Melanoma drugs slow disease, boost hopes for combination therapy’) . But colon cancers with BRAF mutations proved surprisingly wily, and early trials were disappointing. “No one would have expected that five years ago,” says oncologist Keith Flaherty of Harvard Medical School in Boston, Massachusetts. “Melanoma was historically the intractable one, not colon cancer.”

Cancer researcher René Bernards of the Netherlands Cancer Institute in Amsterdam and his colleagues decided to tackle this question using a large genetic screen based on RNA-interference, a technique that can be used to systematically reduce the expression of individual genes.

They found that colon cells with the BRAF mutation became sensitive to vemurafenib when expression of another cancer-associated protein, EGFR, was knocked down. In fact, treatment with vemurafenib activated EGFR in colon tumours, but not in melanoma, where EGFR is expressed only at low levels.

This finding is cause for renewed optimism: there are EGFR-inhibiting drugs already approved for the treatment of cancer. Bernards and his colleagues found that coupling these drugs with vemurafenib shut down the EGFR escape route, suggesting that the 8–10% of colon cancers that carry the BRAF mutation may be once again in the cross hairs. “This observation is so readily translatable, this could be done tomorrow,” says Flaherty, who was not involved with the study but has spearheaded trails of vemurafenib. The drug is also being tested against lung and thyroid cancers with the BRAF mutation.


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