Researchers at UCLA’s Jonsson Comprehensive Cancer Center have discovered the molecular basis behind the relatively high incidence of secondary skin cancers that develop after patients received the drug vemurafenib (Zelboraf, Genentech) for metastatic melanoma, according to findings published today in The New England Journal of Medicine
The pill, taken twice daily, was approved by the FDA in August 2011 to treat patients with BRAF V600E
-positive unresectable or metastatic melanoma. Vemurafenib blocks the mutated BRAF protein, but in doing so, researchers found that it also sets off a chain of events that lead to the development of secondary skin cancers in patients who also carry another predisposing skin cancer mutation.
“We wondered why it was that we were treating and getting the melanoma to shrink, but another skin cancer was developing,” said Antoni Ribas, MD, a professor of Hematology and Oncology at UCLA and lead author of the study, in a statement released on Wednesday. “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.”
The researchers performed a molecular analysis on 21 tumor samples of patients who had been previously treated with vemurafenib. Thirteen of them had RAS
mutations, with 12 of those in HRAS
. A validation set of 14 samples had 8 samples with RAS
mutations, with 4 of those in HRAS
. The most frequent of the RAS
mutations was HRAS Q61L
mutant cell lines exposed to vemurafenib demonstrated increased proliferation that was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of extracellular signal-regulated kinase-mediated transcription.
“Our data indicate that RAS
mutations are present in about 60% of cases in patients who develop skin squamous cell cancers while treated with vemurafenib,” 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.”
When the researchers blocked non-mutated BRAF
in cells that had mutated RAS
, signals were sent around BRAF
, inducing growth of squamous cell cancers.
The researchers suggest a strategy in which a MEK inhibitor is used in addition to vemurafenib before the BRAF
-targeted drug has a chance to induce secondary skin cancer in people with the RAS
Vemurafenib was approved in August based on the results of the BRIM3 trial, which compared vemurafenib to dacarbazine in 675 patients with V600E BRAF
-mutated melanoma. Patients receiving vemurafenib experienced a 74% reduction in disease progression (hazard ratio, 0.26; P
<.0001) with a median progression-free survival of 5.3 months.
The National Cancer Institute estimates that 70,230 men and women were diagnosed with some form of melanoma in 2011, with 8,790 patients dying from the disease.