“BRAF is an oncogenic protein kinase that drives cell growth and proliferation through the MEK-ERK signaling pathway. BRAF inhibitors have demonstrated antitumor efficacy in melanoma therapy but have also been found to be associated with the development of cutaneous squamous cell carcinomas (cSCCs) in certain patients. Here, we report that BRAF is phosphorylated at Ser729 by AMP-activated protein kinase (AMPK), a critical energy sensor. This phosphorylation promotes the association of BRAF with 14-3-3 proteins and disrupts its interaction with the KSR1 scaffolding protein, leading to attenuation of the MEK-ERK signaling. We also show that phosphorylation of BRAF by AMPK impairs keratinocyte cell proliferation and cell-cycle progression. Furthermore, AMPK activation attenuates BRAF inhibitor-induced ERK hyperactivation in keratinocytes and epidermal hyperplasia in mouse skin. Our findings reveal a mechanism for regulating BRAF signaling in response to energy stress and suggest a strategy for preventing the development of cSCCs associated with BRAF-targeted therapy.”
Results are encouraging in an ongoing clinical trial of a BRAF inhibitor combined with a MEK inhibitor, according to a presentation at the 2013 European Cancer Congress in Amsterdam, Netherlands. The BRAF inhibitor is vemurafenib, which is approved by the U.S. Food and Drug Administration (FDA), and the MEK inhibitor is cobimetinib (GDC-0973/XL518), which is experimental. The phase I trial has 128 people with melanomas that have BRAFV600 mutations; about half had been treated with BRAF inhibitors previously, while the other half had not. Tumors shrank in 15% of participants and didn’t grow in 43% of those who had been previously treated with BRAF inhibitors. Even better, tumors disappeared in 10%, shrank in 75%, and didn’t grow in 13% of those who had not been previously treated with BRAF inhibitors.
“Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.”
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.
The U.S. Food and Drug Administration (FDA) has granted a priority review of whether two melanoma drugs work better together. The drugs are a BRAF inhibitor called Tafinlar (dabrafenib) and a MEK inhibitor called Mekinist (trametinib); both are already FDA-approved for use separately. Tumors, however, often become resistant to BRAF inhibitors, growing back after an initial period of shrinking. The hope is that adding a MEK inhibitor will prevent this resistance. The FDA’s ruling on this combination targeted treatment is expected in January 2014.
A new study suggests there may be a way to predict how well a targeted treatment will work against melanomas with BRAF mutations. This finding is from a phase II clinical trial that included 76 people with BRAF V600E mutated melanomas who were treated with dabrafenib, a BRAF inhibitor. Besides confirming the efficacy of dabrafenib, the study showed that the higher the initial level of tumor DNA in the blood, the better dabrafenib worked. That said, the researchers caution that this correlation must be confirmed in a larger study.
While effective against melanomas with BRAF mutations, BRAF inhibitors can also cause other cancers such as squamous cell carcinoma and RAS-mutant leukemia. In an overview of the field, researchers say that people treated with BRAF inhibitors may need long-term follow-ups. The researchers also suggest combining BRAF inhibitors with treatments that target the other cancers. These include MEK inhibitors, which control some but not all of the other cancers. In addition, people treated with BRAF inhibitors may need more aggressive screening if they have a family history of colorectal cancer.