BRAF inhibitors can trigger an undesired, paradoxical activation of the cell cycle, with the result being the occurrence of secondary skin cancers, such as squamous cell carcinoma.
Banff, Alberta - Dermatologists need to monitor their melanoma patients who are taking BRAF inhibitors, for they are at risk of developing multiple squamous cell carcinomas (SCCs) and even new primary melanomas, according to an attending physician at Memorial Sloan-Kettering Cancer Center, New York.
Dr. MarghoobSpeaking at the 8th annual Canadian melanoma conference held here recently, Ashfaq Marghoob, M.D., a board-certified dermatologist and director of Memorial Sloan-Kettering Regional Skin Cancer Clinic in Hauppauge, N.Y., described the paradoxical activation of the cell cycle that can occur while patients with melanoma are on BRAF inhibitor therapy to treat their disease.
The RAS family of proteins relay signals from outside the cell to the cell’s nucleus by interacting with BRAF, which in turn stimulates MEK, which stimulates ERK, eventuating in cell division.
Mutated BRAF can cause the cell cycle to stay active resulting in increased cell division; thus, it stands to reason that the administration of a BRAF inhibitor should shut down this process.
While BRAF inhibitors can halt the cell cycle, there are situations in which these agents can paradoxically activate the cell cycle. This is believed to occur in certain situations such as when there is a mutation in one of the RAS proteins. In the presence of such a mutation, BRAF appears to dimerize with CRAF, and the resultant stimulated CRAF can, in turn, bypass BRAF blockade, causing the cell cycle to remain active.
“In the presence of mutations such as HRAS and NRAS, the door opens for the development of secondary skin cancers, including squamous cell carcinoma and melanoma,” Dr. Marghoob says.
Adding a downstream MEK inhibitor may prevent the development of these secondary skin cancers in patients taking a BRAF inhibitor, Dr. Marghoob says.
“By blocking MEK, it may be possible to prevent the paradoxical stimulation of the RAS-RAF-MER-ERK pathway,” Dr. Marghoob says.
Studies have demonstrated that the addition of a MEK inhibitor results in a lowering of the number of SCCs that develop in patients on BRAF inhibitors.
“Time will tell if the addition of a MEK inhibitor to BRAF inhibitor therapy will also result in the development of fewer new primary melanomas and reduction in the rate of changing nevi,” Dr. Marghoob says.
It has been observed that patients on BRAF inhibitor therapy develop frequent changes in their nevi with nevi disappearing, new nevi appearing and existing nevi becoming larger or darker, Dr. Marghoob explains.
“When you follow patients who are on BRAF inhibitors, you will see this increased nevus volatility or flux,” Dr. Marghoob says. “BRAF inhibitor therapy continues to be investigated to determine the optimal dosing intervals and combination therapies that will produce involution of the primary tumor while at the same time preventing the development of resistance and new primary cancers.”
In the meantime, it seems prudent for physicians to screen patients for skin cancer if they are on a BRAF inhibitor, according to Dr. Marghoob.
“One suggestion is that patients be screened at baseline and then at one month after starting BRAF inhibitor therapy, then at two months, at three months, and then every three to six months thereafter,” Dr. Marghoob says.
Dr. Marghoob referred to a prospective follow-up of pigmented lesions in metastatic melanoma patients on a BRAF inhibitor where digital dermoscopy was employed for surveillance (Perier-Muzet M, Thomas L, Poulalhon N, et al. J Invest Dermatol. 2014;134(5):1351-1358).
Dr. Marghoob reports no relevant financial interests.