Melanoma drugs potentially harmful to some patients

It is well known within the scientific community that the BRAF gene is faulty in approximately half of malignant melanomas and many other cancers, making it a suitable drug target. Drugs that block BRAF function in cells are already showing positive results in early clinical trials in melanoma. While the long-term effects of these drugs are not yet known, two new reports have suggested that these drugs may have unintended consequences in patients whose tumours lack mutations in the BRAF gene.

In separate studies, conducted by researchers in the US, from the Memorial Sloan-Kettering Cancer Center, and the UK, by the Institute of Cancer Research (ICR), scientists tested the drugs to better understand how they behave in cells, and found that they spurred the growth of some tumours. These preliminary findings raise the possibility that certain patients should not receive BRAF inhibitors, as they could make their cancers worse.

Based on these studies, it is thought that giving these drugs to patients whose tumours have normal copies of the BRAF gene could accelerate tumour growth. The findings suggest that physicians need to avoid treating patients who do not have certain genetic mutations, as they could potentially cause harm. The drugs primarily target a mutation in the BRAF gene, called V600E. Many, but not all of the patients enrolled in clinical trials of BRAF inhibitors have had this mutation in their tumours. The alteration is present in approximately half of all melanomas and it activates growth-promoting messages from the MAPK signalling pathway.

The new studies focused on tumours that had mutations elsewhere in the pathway. Both groups found that BRAF inhibitors can promote tumour growth in melanoma cells that lack the V600E mutation by activating other elements of the pathway. The researchers proposed several models that could potentially explain how a drug designed to inhibit the pathway could lead to its activation. The US study's first author, Dr Georgia Hatzivassiliou, of Genentech (Roche), noted that the new results, which were published in the 3rd February online edition of Nature (10.1038/nature08833), clearly indicate that the effects of BRAF inhibitors depend on the cellular context of a tumour cell. For instance, both research teams found that the drugs could activate BRAF signalling in melanoma tumours with mutations in the RAS gene, which is part of the BRAF pathway.

As reported by the ICR in the 22nd January issue of Cell (2010;140:209-221), the drugs fuelled rather than blocked the growth of melanoma cells with RAS mutations. Both studies concluded that a central player in the activation of the BRAF pathway was a protein, called CRAF, which is a close relative of BRAF. These findings provide a framework for understanding possible mechanisms of resistance to BRAF inhibitors and give researchers information about where to look in the signalling pathway.

This work has large implications, with every tumour being different; understanding more surrounding the biology of these tumours may allow scientists to develop better treatment options. Further, the impact of this research will enable physicians to target treatments more precisely to patients who will definitely benefit, and avoid treating those who will not. The financial impact of these findings is at present unknown, however, there are BRAF inhibitors currently in clinical development. Plexxikon's PLX4032 (also known as RG7204), which is in-licensed by Roche, is currently in an open-label, single-arm, Phase II trial, called BRIM2 (B-Raf Inhibitor in Melanoma), in previously-treated metastatic melanoma patients, and recently entered a pivotal Phase III trial, BRIM3, for the same indication.

Alice Rossiter
Editor, Cancer Drug News