Investigators have discovered why the pill Zelboraf (vemurafenib), effective against melanoma, may also cause the development of a secondary skin cancer: squamous cell carcinoma (SCC).

“We wondered why it was that we were treating and getting the melanoma to shrink, but another skin cancer was developing,” commented Antoni Ribas, MD, PhD, in a statement issued by University of California–Los Angeles. Ribas, a professor of hematology/oncology, studies melanoma at the facility’s Jonsson Comprehensive Cancer Center, and served as co-senior author of the paper that revealed the answer to this puzzle (N Engl J Med. 2012;366:207-215).

Zelboraf was approved in August 2011 for the treatment of persons with BRAF mutation–positive melanoma. Approximately 50% of persons with melanoma have this mutation, and an estimated 25% of this patient subset develop skin SCCs.

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Working with investigators from many institutions as well as Hoffmann-La Roche and Plexxikon, Inc., the two drug companies with divisions that co-promote Zelboraf in the United States, Ribas’s team learned that the very action by which vemurafenib works—blocking the mutated BRAF protein in melanoma cells—triggers a cellular cascade in other skin cells that have another predisposing genetic mutation, RAS. This ultimately accelerates the development of the secondary skin cancers.

Among 21 tumor samples studied in this project, 13 had RAS mutations. A different set of 14 tumor samples revealed 8 with RAS mutations; thus, 60% (21 of 35) of the specimens harbored RAS mutations.

Strategies are being developed to inhibit the BRAF mutation with vemurafenib and block the cellular cascade with an agent known as an MEK inhibitor before the cascade initiates secondary skin cancers.