(HealthDay News) – Combining the BRAF inhibitor vemurafenib with an MEK inhibitor may help prevent squamous-cell carcinomas in melanoma treatment, according to a study published in the January 19 issue of the New England Journal of Medicine.
Fei Su, Ph.D., from Hoffmann-La Roche in Nutley, N.J., and contributors from numerous cancer research centers performed a molecular analysis of patient lesions to independently evaluate treatments with the BRAF inhibitor vemurafenib in the presence of oncologic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53). The researchers found that 21 of 35 tumor samples (60 percent) tested positive for RAS mutations, the most prevalent being HRAS Q61L, and that mutant cell lines exposed to the BRAF inhibitor were associated with mitogen-activated protein kinase (MAPK). In a mouse model, the investigators further noted that vemurafenib didn’t promote carcinogenesis but accelerated growth of lesions harboring HRAS mutations, which could be blocked by treatment with another inhibitor (MEK).
“Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib,” the authors write. “The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions.”
The study was funded in part by Hoffmann-La Roche and Plexxikon; several authors disclosed financial relationships with pharmaceutical companies, including Hoffmann-La Roche and Plexxikon.