Blocking CRAF activity prevents natural BRAF-inhibition, according to Molecular Cell paper.

Scientists have uncovered an unexpected interaction between the CRAF and BRAF kinases that may explain why the globally marketed kidney and liver cancer drug, Nexavar, failed in Phase III melanoma trials. The findings suggest that a new generation of more selective RAF kinase blockers may have better success against some types of cancer.

Nexavar, a drug developed jointly by Bayer and Onyx Pharmaceuticals, is a multi-RAF inhibitor that primarily targets CRAF and to a lesser extent BRAF, according to researchers at Cancer Research UK’s Cambridge Research Institute. Mutations in BRAF can promote cancer cell growth via the MAPK pathway and have been linked to about 70% of melanomas.

The Cambridge team has now found that CRAF naturally interacts with and inhibits the activation of mutated BRAF in melanoma cell lines. This unexpected finding suggests that in cases of melanoma at least, using drugs that inhibit CRAF may actually prevent the kinase from doing its natural anticancer job of blocking renegade BRAF.

More selective BRAF inhibitors should fare better against melanoma, points out David Tuveson, Ph.D., head of the experimental medicine laboratory at the Cambridge facility and lead author of Molecular Cell paper titled “C-Raf Inhibits MAPK Activation and Transformation by B-RafV600E.”

“Previous studies on CRAF suggested it can cause cancerous changes to develop, so drugs were developed to tackle this,” Dr. Tuveson explains. “To our surprise, we can now see that CRAF actually helps control cancer in some situations such as when the BRAF gene is mutated in melanoma. Strangely, in this case, two wrongs make a right.”

Dr. Tuveson stresses that further work will be needed to clarify the situation. However, he maintains that if the hypothesis is correct, a new generation of kinase inhibitors designed specifically to switch off BRAF and leave CRAF alone “will have more success in controlling the cancer.”

Nexavar was first approved in 2005 and is now sanctioned in over 80 countries for the treatment of renal cell and/or hepatocellular carcinoma. Bayer and Onyx are also carrying out clinical trials in other cancers including thyroid, breast, ovarian, and non-small-cell lung cancers. In October the companies started an international Phase III trial evaluating Nexavar in patients with radioactive iodine-refractory, locally advanced, or metastatic-differentiated thyroid cancer.

Earlier in April, however, the companies confirmed that they were halting a Phase III trial evaluating Nexavar in combination with chemotherapy against melanoma. An interim review showed that the study would not meet its primary endpoint of overall increased patient survival compared with chemotherapy alone.

Nexavar is Onyx’ key asset and represented Bayer’s sixth best-selling pharmaceutical last year. Under the terms of their agreement, Bayer and Onyx each fund 50% of development costs worldwide, excluding Japan, where Bayer funds all product development. The companies are co-promoting the drug in the U.S. and equally share relevant profits. Outside the U.S., Bayer has exclusive marketing rights, and shares profits equally with Onyx. In Japan, though, Onyx receives a royalty. Global sales of Nexavar reached $678 million in 2008, up from $372 million in 2007.

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