A new class of drugs may join the ranks of personalized therapies.
Tumors with a mutated BRAF gene are especially sensitive to drugs that inhibit the Mek protein, according to research led by Memorial Sloan-Kettering Cancer Center scientists and published this week in an advance online issue of Nature. Both BRAF and MEK are part of the same biological pathway as the pharmacogenomic favorite, EGFR.
David Solit, an assistant member of the cancer center's Department of Medicine, and colleagues in the Cancer Genome Project have been searching for targeted therapies involving MEK-inhibiting drugs that are effective in tumors having mutations in the pathway shared by MEK and EGFR. Using both conventional means, with known cells and compounds, as well as a bioinformatics method employing the US National Cancer Institute's NCI-60 cell lines, they have identified several, Solit told Pharmacogenomics Reporter.
"There was a drug that we were working with [that] inhibits MEK, and we found that these BRAF-mutant tumors are particularly dependent upon this MEK protein," which is not entirely surprising, Solit said. "What is kind of surprising is that the RAS-mutant tumors are not," he said.
It is widely believed that RAS mutants are ultimately responsible for MEK activation, but drug developers should pay special attention to mutated BRAF if they are pursuing MEK inhibitors, said Solit. Only some RAS-mutant tumor cells depend upon MEK for growth, "so inhibiting them with a MEK inhibitor is not always effective with a RAS mutant tumor, but is universally effective — in our hands — with a BRAF mutant tumor," Solit added.
RAS-mutant tumors are inconsistent in their MEK-inhibitor response, while most other tumors are resistant, Solit said.
In a conventional model of the EGFR pathway, the three RAS gene products activate three separate RAF gene products, which in turn activate MEK, stimulating eventual unregulated cell growth through the proteins MAP kinase and ERK. (Click here for an animated depiction of the EGFR pathway created by Expert Reviews in Molecular Medicine; note that the three types of Ras and Raf protein are represented by one protein each.)
The researchers' results are soon going to be put to work for drug development, but not prospectively. "There are some MEK inhibitors that are in clinical [trials] — there's one from Pfizer that we worked with [in research], called PD0325901," Solit said. "The way [Pfizer is] designing it is, they're essentially putting [in the trial] patients with lung cancer, melanoma, or colon cancer — they're primarily going for tumors that have an incidence of these mutations in RAF and RAS — and then they're going to retrospectively look back and see if the patients with mutations are more likely to respond," he said. But the company has not agreed at this point to conduct a trial with patients having only BRAF-mutant tumors, he added.
Another compound under development by AstraZeneca and Array Biopharma, Array 142886, specifically inhibits MEK, as well, Solit said. "So there are going to be at least two drugs that are going after this target. The Pfizer drug is a little bit further ahead — it's starting Phase II — and the other one's in Phase I still," he said.
To identify mutations corresponding to MEK-inhibitor sensitivity, the researchers initially worked with known drugs in known cell lines, but they followed up with a fairly fresh technique. The group downloaded the US National Cancer Institute's data on its NCI-60 cell lines' response to approximately 40,000 compounds, then genotyped the NCI-60 panel for RAS and BRAF mutations. Using a sorting-analysis bioinformatics technique, the researchers identified compounds that specifically inhibited all BRAF-mutant tumor cells, but no others.
The method may prove to be a powerful way to target anti-cancer compounds tested on the NCI-60. "It happens to turn out that a lot of the compounds on that list are known MEK inhibitors, so it was a second way to identify the same thing that we found," Solit said. "We identified 36 compounds in total that specifically go after tumors that have this BRAF mutation," some of them known MEK inhibitors, and some not, he said. "And it's possible we could go back and look at those compounds now, as ones that could be developed for tumors that have this mutation."
— Chris Womack ([email protected])