Patients with deadly metastatic melanoma who take the recently FDA-approved drug, vemurafenib, marketed under the brand name Zelboraf, are realizing an improved overall survival, but patients developed a secondary skin cancer, a new study says.
Now researchers at UCLA’s Jonsson Comprehensive Cancer Center, working with investigators from the Institute of Cancer Research in London and drug makers Roche and Plexxikon, have new understanding of how vemurafenib’s melanoma-fighting mechanism also allows for the development of secondary squamous cell carcinomas.
The researchers wanted to know why melanoma tumors were shrinking but another type of skin cancer was developing.
“We looked at what was likely making them grow and we discovered that the drug was making preexisting cells with a RAS mutation grow into skin squamous cell cancers,” said Dr. Antoni Ribbas, who studies melanoma at the Jonsson Cancer Center and is co-senior author of the paper and a UCLA professor of hematology and oncology.
The very action by which the twice-daily pill works — blocking the mutated BRAF protein in melanoma cells — sets off a cellular cascade in other skin cells if they have another predisposing cancer mutation. Ultimately, these cellular cascades accelerate the development of secondary skin cancers.
“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.”
About 50 percent of patients who get melanoma have the BRAF mutation and can be treated with vemurafenib, Dr. Ribas said. Of those, a quarter of the patients develop skin squamous cell carcinomas. "The squamous cell carcinomas were removed surgically, and vemurafenib was not discontinued for this side effect."
It’s rare for oncologists to understand molecularly why a side effect to cancer treatment is happening, Dr. Ribas said.
Ribas and colleagues found that blocking the non-mutated BRAF in cells with mutated RAS caused them to send signals around BRAF that induced the growth of the squamous cell cancers.