New melanoma drug Vemurafenib accelerates secondary skin cancers

Ernie Shannon's picture
Vemurafenib linked to second skin cancer

A potential nightmare for skin cancer patients has been partially resolved.

Researchers in Los Angeles and London, England have discovered what they believe is the cause of a secondary skin cancer often erupting in patients being treated for metastatic melanoma. People taking the recently approved drug Vemurafenib sometimes develop skin squamous cell carcinomas.

Scientists from UCLA’s Jonsson Comprehensive Cancer Center and the Institute of Cancer Research in London determined that while the twice daily pill, Vemurafenib, successfully blocks the mutated BRAF protein in melanoma cells, the blocking mechanism begins a cellular cascade in other skin cells. If those cells have a predisposed cancer mutation, then the secondary skin squamous cell carcinoma develops.

“We wondered why it was that we were treating and getting the melanoma to shrink, but another skin cancer was developing,” said Dr. Antoni Ribas, co-senior author of the paper and a professor of hematology/oncology at the Jonsson Cancer Center. “We looked at what was likely making them grow and we discovered that the drug was making pre-existing cells with a RAS mutation grow into skin squamous cell cancers.”


Ribas, who studies melanoma at the cancer center, said about 50 percent of patients who get melanoma have the BRAF mutation and can be treated with Vemurafenib. Of those, a fourth of the patients develop the secondary cancer.

“Our data indicate that RAS mutations are present in about 60 percent of cases in patients who develop skin squamous cell cancers,” Ribas continued. “This RAS mutation is likely caused by prior skin damage from sun exposure, and what Vemurafenib does is accelerate the appearance of these skin squamous cell cancers, as opposed to being the cause of the mutation that starts these cancers.”

The work by the teams separated by continents, but closely aligned strategically, provided a rare look at the molecular development of cancer. The combined team performed a molecular analysis to identify the oncogenic mutations in the squamous cell lesions of patients treated with the BRAF inhibitor. Ribas said among 21 tumor samples, 13 had RAS mutations and in another set, eight of 14 samples had the RAS mutations. The investigators found that blocking the non-mutated BRAF in cells with mutated RAS caused them to send signals around the BRAD that induced the growth of the squamous cell cancers. This discovery has led to strategies to inhibit both the BRAF mutation with Vemurafenib and block the cellular cascade with a different drug, a MEK inhibitor, before it initiates the second skin cancers. Studies are now underway testing BRAF and MEK inhibitors in combination in patients with metastatic melanoma.

“By understanding the mechanism by which these squamous cell cancers develop, we have been able to devise a strategy to prevent the second tumors without blocking the beneficial affects of the BRAF drugs,” said senior co-author Dr. Richard Marais from the Institute of Cancer Research in London. Marais developed an animal model for the study.

The study was supported by Roche, Plexxikon, the Seaver Institute, the Louise Belley and Richard Schnarr Fund, the Fred L. Hartley Family Foundation, the Wesley Coyle Memorial Fund, the Ruby Family Foundation, the Albert Stroberg and Betsy Patterson Fund, the Jonsson Cancer Center Foundation and the Caltech-UCLA Joint Center for Translational Medicine.