We already knew that melanomas can resist BRAF inhibitor drugs by activating a particular cancer pathway (a group of proteins in a cell that work together to control cell multiplication, which can lead to tumor growth)—but new research shows that this resistance can also be caused by activating a second cancer pathway. The first pathway is called MAPK and the second is called PI3K-PTEN-AKT. The researchers studied 100 melanomas that resisted the BRAF inhibitors vemurafenib or dabrafenib, and found that 70% had mutations in the first pathway, while 22% had mutations in the second pathway. Moreover, mutations in both pathways could occur in the same tumor, suggesting that thwarting resistance to BRAF inhibitors may require targeting both pathways with a combination treatment.
Two new studies show that several different genetic mutations can make melanoma tumors resist drugs known as BRAF inhibitors, complicating treatment. These mutations are in genes that are part of the ‘MAPK pathway.’ The first study was on BRAF-inhibitor resistant melanomas from 45 people. In about half of the tumors, one of a set of three genes (MEK1, MEK2, MITF) was abnormal, and in three of the tumors more than one was abnormal.
The second study compared melanomas before and after resistance to combination treatment with both BRAF and MEK inhibitors. Tumors from three of the five people in the study developed genetic abnormalities that were not seen before treatment. On a positive note, when cells from resistant melanomas with both BRAF and MEK mutations were grown in the laboratory, they responded to a drug that inhibits a related protein called ERK.
The mutations in this study were all found in genes that code for proteins in the MAPK pathway, a particular group of proteins in a cell that work together to control cell multiplication that can lead to tumor growth. Knowing exactly which mutations a melanoma has will help doctors target it with the right combination of treatments.
Melanomas with BRAF mutations often become drug-resistant, but now researchers think they know how to tell who will benefit from continued treatments. The researchers studied BRAF-mutant melanomas in nine people before and after targeted treatment, and found that tumors were less likely to grow when a protein called S6 was not activated. Next, the researchers developed a way to monitor S6 — and so tumor response —in treated melanomas in real-time. Their method entails fine-needle aspiration, which is far less invasive than conventional biopsies and could potentially replace the serial biopsies currently done to test for tumor resistance.
Melanomas commonly stop responding to targeted therapies, and a new study helps explain why. The researchers linked resistance to BRAF and MEK inhibitors in people with two genetic abnormalities: extra copies of BRAF-V600E, the most common melanoma mutation, as well as a new mutation called MEK2-Q60P. Encouragingly, the researchers also found that adding a third treatment (a PI3K inhibitor) to the mix makes melanomas stop growing in mice. While the team cautions that the solution is unlikely to be as simple of a triple inhibitor treatment for people, this work could help researchers find ways of overcoming drug resistance in melanomas.
Like other tumors, advanced melanomas include a mix of cells with different genetics and behaviors. For example, some melanoma cells don’t divide rapidly. These differences can help some melanoma cells evade targeted therapies, making it impossible to kill off the tumor. Now, researchers report a new combination treatment that sidesteps resistance: methotrexate, a conventional chemotherapy drug, and TMECG, a new toxic molecule made by the researchers. Methotrexate pushes melanoma cells to divide and to make a protein called tyrosinase. The new toxic molecule TMECG is activated by tyrosinase, and so then targets the melanoma cells. Besides being specific to melanomas, this new combination treatment works on tumors that have resisted all other therapies.
The drug vemurafenib targets melanomas with BRAF mutations, but treatment usually stops working after just 6 to 8 months because tumors become drug-resistant. However, resistance could be avoided by giving people periodic breaks from treatment, suggests work presented at the 2013 meeting of the American Association for Cancer Research. The researchers found that stopping treatment slowed tumor growth in 14 out of 19 people with vemurafenib-resistant melanomas. They also found that intermittent treatment (4 weeks on and 2 weeks off) prevented vemurafenib resistance in human melanomas implanted in mice. This strengthens the researchers’ previous work showing that vemurafenib-resistant melanomas actually depend on the drug to grow.
An experimental drug may strengthen treatments that target melanomas with mutations in the BRAF gene, reported researchers from the pharmaceutical company Merck at the American Association for Cancer Research’s 2013 meeting. Treatments that target BRAF often stop working because tumors activate a related protein called ERK, which is the target of Merck’s new drug. Called SCH772984, the drug inhibits ERK in cultured human tumor cells with BRAF, NRAS, or KRAS mutations; slows cell division in human tumor cells that resist treatments that target BRAF or MEK; and shrinks tumors in mice. The researchers have begun a phase I clinical trial of an ERK inhibitor in people with tumors.