Melanoma Drugs Have Unintended Effects in Some Tumors
Some patients with advanced melanoma have had dramatic responses to a new class of targeted drugs in early stage clinical trials. While the long-term effects of these drugs, called BRAF inhibitors, are not yet known, two reports suggest that these drugs may have unintended consequences in patients whose tumors lack mutations in the BRAF gene.
In separate studies, scientists in Great Britain and the United States tested the drugs in the laboratory to better understand how BRAF inhibitors behave in cells. To their surprise, the drugs actually spurred the growth of some tumors. The preliminary findings raise the possibility that certain patients should not receive BRAF inhibitors because the drugs could make their cancers worse.
Based on these studies, there is reason to suspect that giving these drugs to patients whose tumors have normal copies of the BRAF gene could actually accelerate tumor growth, said Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center, who has led clinical trials of BRAF inhibitors but was not involved in these studies. “The findings suggest that we need to avoid treating patients who do not have certain genetic mutations because you could potentially do harm,” he added.
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 tumors. The alteration is present in approximately half of all melanomas, and it activates growth-promoting messages from the MAPK signaling pathway.
The new studies focused on tumors that had mutations elsewhere in the pathway. “Both groups found that BRAF inhibitors can promote tumor growth in melanoma cells that lack the V600E mutation by activating other elements of the pathway,” said Dr. Shiva Malek of Genentech, who led one of the studies.
Reporting their findings online in Nature on February 3, the researchers proposed several models that could potentially explain how a drug designed to inhibit the pathway could lead to its activation.
“Our results are certainly paradoxical,” said the study’s first author, Dr. Georgia Hatzivassiliou of Genentech. “You expect an inhibitor to be an inhibitor under any circumstance.” But she noted that the new results clearly indicate that the effects of BRAF inhibitors depend on the cellular context, or the genetic background of a tumor cell.
Both groups found, for instance, that the drugs could activate BRAF signaling in melanoma tumors with mutations in the RAS gene, which is part of the BRAF pathway. As the British researchers reported in the January 22 Cell, the drugs fueled rather than blocked the growth of melanoma cells with RAS mutations.
The study’s lead investigator, Dr. Richard Marais of the Institute of Cancer Research in the United Kingdom, said in a statement that the new findings would give researchers insights into how BRAF drugs will behave in humans. Both studies, for instance, concluded that a central player in the activation of the BRAF pathway was a protein called CRAF, which is a close relative of BRAF.
“The findings provide a framework for understanding possible mechanisms of resistance to BRAF inhibitors,” said Dr. Chapman. “The results give researchers an idea where to look in the signaling pathway.”
Dr. Neal Rosen, also at Memorial Sloan-Kettering, published a study last year describing some of the complexities of the BRAF pathway. He and others have been investigating the genetic alterations that confer resistance to these drugs, but progress has been slow because it has been difficult to obtain enough tumor samples from patients with melanoma who developed resistance to BRAF inhibitors, noted Dr. Chapman.
That could eventually change as new clinical trials of BRAF inhibitors move forward, including a phase III study that is expected to open soon.
“The bottom line for patients is that we’ve made great strides in developing drugs to target this pathway,” said Dr. Malek. “But we can always do better. Every tumor is different, and understanding more about the biology of these tumors will allow us to develop smarter interventions.”
—Edward R. Winstead