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. The 18-month study appears in the Jan. 19, 2012 edition of the New England Journal of Medicine.
“Our data indicate that RAS mutations are present in about 60 percent of cases in patients who develop skin squamous cell cancers while treated with vemurafenib,” Dr. 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.”
Professor Richard Marais of the Institute of Cancer Research in London, the paper’s co-senior author, says 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.
“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,” Marais said. “This may allow many more patients to benefit from these important drugs.”
Studies currently are underway testing BRAF and MEK inhibitors in combination in patients with metastatic melanoma.
The National Institutes of Health has much more information on skin cancer at http://health.nih.gov/topic/SkinCancer/
Lynette Summerill, an award-winning writer and scuba enthusiast lives in San Diego, CA with her husband and two beach loving dogs. In addition to writing about cancer-related issues for EmpowHER, her work has been seen in newspapers and magazines around the world.
Sources:
RAS Mutations in Cutaneous Squamous-Cell Carcinomas in Patients Treated with BRAF Inhibitors. New England Journal of Medicine. Antoni Ribas, M.D., Ph.D., and Richard Marais, Ph.D. et al. Engl J Med 2012; 366:207-215. Abstract and article accessed online 30 January 2012 at: http://www.nejm.org/toc/nejm/366/3
UCLA News. UCLA Research Uncovers Drug Mechanism. Roxanne Moster. 18 January 2011. Accessed online 30 January 2012 at: http://www.cancer.ucla.edu/index.aspx?recordid=548&page=644
Reviewed January 31, 2012
by Michele Blacksberg RN
Edited by Jody Smith