Scientists have identified two molecular targets in some forms of skin cancer, which they say could lead to new treatment options for the disease. This is according to a study published in the the journal Clinical Cancer Research.
According to the research team from the Vanderbilt-Ingram Cancer Center in Tennessee, around 35% of skin cancer cases are thought to be “pan-negative.” This means they are free from mutations in the genes BRAF, NRAS, KIT, GNAQ and GNA11.
Because of this, the investigators wanted to analyze patients with melanoma tumors that were pan-negative, in order to better understand activity in these tumors and how they could be targeted in terms of treatment.
The researchers used a process called “targeted next-generation sequencing” to analyze the tumors. From this, they found that around of 8% of pan-negative tumors consist of BRAF fusions.
These fusions are defined as two or more genes that link together to create abnormal proteins that can prompt the development of cancer.
Commenting on this discovery, Prof. Jeffrey A. Sosman of the Vanderbilt-Ingram Cancer Center and study author, says:
“Our results are important because they obviously suggest that there probably are other, as yet unidentified, molecular changes that make these melanomas susceptible to drugs that are available right now.”
BRAF fusions trigger cancer cell pathway
Further research on one of the pan-negative melanoma samples revealed a fusion between two genes – PAPSS1 and BRAF. Additional analysis of 24 pan-negative samples revealed one other BRAF fusion between the genes TRIM24 and BRAF.
The investigators then discovered that both of these BRAF fusions triggered a pathway in melanoma cancer cells called the MAPK signaling pathway.
Some of the cancer cells were then treated with vemurafenib – a BRAF inhibitor. Others were treated with trametnib – a drug that erases a protein called MEK in the MAPK pathway.
The researchers discovered that the MAPK signaling pathway triggered by the BRAF fusions could be inhibited by trametnib. This indicated that the fusions were able to make melanoma cells sensitive to MEK inhibitors.
The MAPK signaling pathway did not show any response to vemurafenib.
Prof. Sosman, also an investigator of the Stand up to Cancer Melanoma Dream Team, says the discovery of the BRAF fusions suggest there may already be drugs available to treat these pan-negative melanomas.
“Currently, there is immense value in identifying novel mutations in untreatable cancers because many of them are clinically relevant, which means they may be sensitive to drugs that are either being developed or are already FDA approved.
Our data support the idea that ‘pan-negative’ cancers are not truly pan-negative.”