Roche melanoma pill spurs growth of other cancers

The recently approved drug vemurafenib (Zelboraf) has been hailed as a breakthrough in the treatment of melanoma, the deadliest form of skin cancer. But roughly one-quarter of patients who take the medication develop a troublesome side effect: secondary skin cancers called squamous cell carcinomas.


Now, a new study by researchers at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, and colleagues identifies the specific genetic mechanism that causes this side effect.
"What we found is that vemurafenib blocks the mutation that makes the melanoma grow, but when patients have skin cells with another mutation that's probably induced from sun exposure, there the drug has the exact opposite effect and causes these squamous cell cancers to grow," said Dr. Antoni Ribas, co-senior author of the study and an associate professor of hematology/oncology at UCLA.


To understand why, the team -- which included researchers from the University of California, Los Angeles, Roche and Daiichi Sankyo's Plexxikon -- studied squamous cell cancer tissue from 21 malignant melanoma patients who had been treated with vemurafenib in a clinical trial.


They found about 60 percent also had RAS mutations, likely caused by sun exposure, that could predispose them to squamous cell cancer. And unlike melanoma cells, when these mutated cells became exposed to a BRAF inhibitor, they tend to grow.


"It's not that these drugs (BRAF inhibitors) are tumor promoters. What they do is accelerate growth of preexisting but asymptomatic tumors in the skin of patients who are susceptible to that disease," he said.


Treatment with a MEK inhibitor blocks this side effect, Marais said.


Tests in lab mice found that those with both types of skin cancers who were treated with a combination of a BRAF and MEK drug had fewer lesions.


And there are hints that process may work in people.


In June, GSK presented the first data from its combination BRAF and MEK inhibitors at the American Society of Clinical Oncology meeting.


"One of the things they found is the patients had fewer skin lesions. It actually works in people," Marias said.


He said the findings may spur more companies to combine their BRAF and MEK inhibitors.


"Not only will it give you the best response but it won't give you the secondary events," he said.


Melanoma globally afflicts nearly 160,000 new people each year. It can spread quickly to internal organs and average survival is six to nine months.