R&D News: Researchers uncover how vemurafenib enhances secondary skin cancers

The research team has worked with investigators from the Institute of Cancer Research in London, Roche and Plexxikon.

The very action by which the drug works sets off a cellular cascade in other skin cells and ultimately accelerates the secondary skin cancers, said Antoni Ribas, co-senior author of the paper and a UCLA professor of hematology-oncology.

About 50 percent of patients who get melanoma have the BRAF mutation and can be treated with vemurafenib, Mr Ribas said. Of those, approximately one-fourth develop skin squamous-cell carcinomas. In study subjects, the squamous-cell carcinomas were removed surgically, and the use of vemurafenib was not discontinued because of this secondary skin cancer side effect.

“We wondered why it was that we were treating and getting the melanoma to shrink but another skin cancer was developing,” said Mr Ribas. “We looked at what was likely making them grow, and we discovered that the drug was making preexisting cells with an RAS mutation grow into skin squamous-cell cancers.”

The combined research team performed a molecular analysis to identify the oncogenic mutations in the squamous-cell lesions of patients treated with vemurafenib. Among 21 tumor samples studied, 13 had RAS mutations. In another set of 14 samples, eight had RAS mutations, Mr Ribas said.

"Our data indicate that RAS mutations are present in about 60 percent of cases in patients who develop skin squamous-cell cancers while being treated with vemurafenib,” Mr Ribas said. “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.”

Mr Ribas’ group found that blocking the non-mutated BRAF in cells with mutated RAS in an animal model caused them to send signals around BRAF that induced the growth of the squamous-cell cancers.

The discovery of the squamous-cell cancer mechanism 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 secondary skin cancers, said co-senior author Richard Marais, a professor at the Institute of Cancer Research in London, who developed the animal model for the study.

“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 effects of the BRAF drugs,” Mr Marais said. “This may allow many more patients to benefit from these important drugs.”

Mr Ribas said that this is one of the very few times that oncologists understand molecularly why a side effect to cancer treatment is occurring.

“The side effect in this case is caused by how the drug works in a different cellular setting,” he said. “In one case, it inhibits cancer growth, and in another, it makes the malignant cells grow faster.”

Studies currently are under way testing BRAF and MEK inhibitors in combination in patients with metastatic melanoma, Mr Ribas said.

“Our data provide a molecular mechanism for the clinical toxicity of a targeted oncogene inhibitor that apparently contradicts the intended effects,” the study states.

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