According to a study conducted by Cancer Research UK, different genetic mutations powering skin cancer may have an impact on how patients respond to the drug vemurafenib, meaning that individuals suffering from melanoma skin cancer should be screened prior to treatment.

The team found that certain rare gene mutations in the tumors of patients receiving the drug may also explain why some patients go on to develop secondary non-melanoma skin cancers. The study is published in the journal Genes and Development.

The drug targets a common defect in the gene BRAF, called V600E. Vemurafenib works by stopping BRAF from stimulating a vital pathway that powers cancer growth.

However, this mutation is not present in all individuals who develop melanoma. Approximately 18% of patients who receive vemurafenib subsequently develop other, less serious, forms of non-melanoma skin cancer, called squamous cell carcinoma, which require surgical removal.

Researchers based at the University of Leicester set out to determine why by studying a group of mice with rare inherited developmental disorders called RASopathies. RASopathies are also caused by mutations in the BRAF gene, although not in the common mutation that causes melanoma.

The researchers looked at a specific rare mutation in BRAF called L597V, which is found in both individuals with RASopathies and patients with melanoma.

The team discovered that the rare mutation did not cause cancer on its own. However, when a second gene, called RAS, was also mutated, the mice developed cancers similar to those caused by the common mutation. In addition, the team found that although the tumors were comparable, the biology powering the cancers was slightly different.

According to the researchers, this means that vemurafenib had reverse effects on cells with the rare fault in BRAS, meaning that in actually increased cancer growth.

Dr. Catrin Pritchard, from the University of Leicester, explained:

“This study shows that the L597V fault only leads to cancer when it happens alongside other faults in the cell, explaining why people with RASopathies don’t usually develop the disease.

But because this rare fault works in a different way from the common one, vemurafenib has the opposite effect and actually causes secondary tumors, albeit less serious non-melanoma ones. This suggests that people should be screened to see what faults they have before they are given vemurafenib.”

Dr Julie Sharp, senior science information manager at Cancer Research UK, said: “Cancer Research UK scientists were among the first to discover the link between melanoma and faulty BRAF, and since then drugs like vemurafenib, which block this pathway, have proved to be a major leap forward in the treatment of advanced melanoma. These results, however, could explain why vemurafenib is less effective in some patients who go on to develop secondary cancers. We now need clinical trials to see whether analyzing BRAF faults can help predict response to vemurafenib in people, as well as mice.”

Written by Grace Rattue