My previous post discussing, among other things, the uncertain impact of mutations in BRAF on melanoma, was written in ignorance of two new and quite relevant papers. One, by Solit et al., and published online in Nature, discusses BRAF in the context of one of its downstream effectors, MEK. The authors show that BRAF mutation is associated with “enhanced and selective sensitivity to MEK inhibition”. Targeting MEK with a specific inhibitor called PD0325901 (Pfizer) completely blocks the growth of xenograft tumors in mice driven by the common V600E mutation in BRAF. They conclude:

Thus far, the use of BRAF inhibitors in clinical trials has met with mixed results. On the other hand, the favourable therapeutic index and selectivity of MEK inhibitors may provide an appealing therapeutic strategy for BRAF mutant cancers. We therefore propose clinical trials of MEK inhibitors in which patients are stratified based on BRAF mutational status.

The second paper, by Curtin et al., and published in The New England Journal of Medicine, describes an array CGH-based assessment of copy number alterations in melanoma. The results show that while BRAF or N-RAS are mutated in more then 80% of melanomas without chronic sun-induced damage, the majority of melanomas in other categories did not have such mutations, but were often associated with amplifications of the genes encoding CDK4 and cyclin D1, both of which are downstream effectors of the RAS–BRAF pathway.

The lesson here is not a new one. As was the case with chemotherapeutic agents like Herceptin for breast cancer and Iressa for lung cancer, the first drug for melanoma will almost certainly not be effective in all cases, but will have to be targeted to those individuals bearing certain mutations. BRAF still points the way.