Zelboraf Side Effects, RAS Mutations, & Squamous Cell Carcinomas

Scientists find out why melanoma drug causes other skin cancers: It’s been acclaimed as a leap forward in the treatment of deadly malignant melanomas, but the recently approved drug Zelboraf (vemurafenib) causes secondary skin cancers as a side effect: About a quarter of patients who take the drug develop squamous cell carcinomas.

Now researchers at the Jonsson Comprehensive Cancer Center at the University of California in Los Angeles may have discovered a way to stop this.

The study, published in the New England Journal of Medicine, 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,” says Dr. Antoni Ribas, the study’s co-senior author and an associate professor of hematology/oncology at the Jonsson Comprehensive Cancer Center.

“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,” Dr. Ribas says.

“This is one of the very few times that we understand molecularly why a side effect to cancer treatment is happening. The side effect in this case is caused by how the drug works in a different cellular setting. In one case it inhibits cancer growth and in another it makes the malignant cells grow,” he adds.

But combining vemurafenib — a BRAF inhibitor — with a drug that blocks the other mutation — a MEK inhibitor — prevents this side effect, researchers found. What’s more, it may also lead to an even more effective melanoma treatment, Ribas says.

“It needs to be demonstrated in clinical trials, but the theory is that if we give these two medications together up front, we will be punching the melanoma where it really hurts twice, and also preventing growth of secondary skin cancers,” Ribas says.

Nearly 160,000 people worldwide are afflicted every year by melanoma, the deadliest form of skin cancer.

Zelboraf is targeted for patients with tumors that have a mutation in a gene known as BRAF that allows melanoma cells to grow. About half of all melanoma patients have the genetic aberration the drug targets.

The twice-daily pill is designed to be used together with a diagnostic test that identifies which patients have the BRAF genetic mutation. It was approved by the European Medicines Agency last December (2011), following approval by the United States Food and Drug Administration in August.

But between 15 percent and 30 percent of patients treated with BRAF inhibitors develop squamous cell carcinomas, a less serious form of skin cancer that needs to be surgically removed.

The new study sought to explore why this happens and what could be done to prevent it.

Researchers at The Institute of Cancer Research led by UCLA’s Dr. Ribas, looked at squamous cell carcinoma tissue taken from 21 malignant melanoma patients who had been treated with Zelboraf in a clinical trial.

They found that almost all samples had mutations in a second gene — known as a RAS mutation — that predisposes people to develop squamous cell cancer. In a set of 21 tumor samples, researchers found 13 with the RAS mutation. In a separate set of 14 samples, eight had RAS mutations.

“Our data suggest that about 60 percent of patients who develop skin squamous cell cancers while treated with a BRAF inhibitor have an RAS mutation,” Ribas says.

RAS mutations are likely to have been caused by prior skin damage from sun exposure, explains Dr. Ribas.