Vemurafenib-associated keratoses with genetic heterogeneity of RAS.
Vemurafenib is a recently approved targeted therapy for advanced melanoma harboring the B-Raf valine-to-glutamate mutation at residue 600 (V600E). In many patients, the use of vemurafenib leads to a rapid onset of cutaneous neoplasms, including squamous cell carcinomas, keratoacanthomas, and benign keratoses. Paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway by vemurafenib in the setting of RAS hyperactivation has been demonstrated in the laboratory and may account for the pathogenesis of some of these neoplasms. Activating RAS mutations have been discovered in vemurafenib-associated squamous cell carcinomas, but have not been reported in benign keratoses, which are a more common side effect that affects patient quality of life. Here, we report on the mutational analysis of RAS genes at known activating hotspots in verrucous keratoses from a stage IV melanoma patient undergoing vemurafenib therapy. The results lend genetic evidence to the current hypothesis for how some of these lesions develop and suggest potential strategies in the research on preventive and therapeutic measures.
Ern
E
Loh
Gregory A
GA
Hosler
D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000009:adverse effects*; D007642:Keratosis / Q000139:chemically induced / Q000235:genetics*; D008545:Melanoma / Q000188:drug therapy*; D008565:Membrane Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012878:Skin Neoplasms / Q000188:drug therapy*; D013449:Sulfonamides / Q000009:adverse effects*; D000077484:Vemurafenib; D018631:ras Proteins / Q000235:genetics*
D000970:Antineoplastic Agents; D007211:Indoles; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; D000077484:Vemurafenib; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins