Long-term effects of BRAF inhibitors in melanoma treatment: friend or foe?
| Autor: | Geoffrey T. Gibney, Inna V. Fedorenko, Sarah Sloot, Keiran S.M. Smalley |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Proto-Oncogene Proteins B-raf
MAPK/ERK pathway Indoles Skin Neoplasms endocrine system diseases Combination therapy MAP Kinase Signaling System paradoxical oncogenesis Hyperkeratosis Cell Antineoplastic Agents BRAF Oximes melanoma medicine Humans Pharmacology (medical) Neoplasm Metastasis dabrafenib MEK INHIBITION skin and connective tissue diseases Vemurafenib Protein Kinase Inhibitors neoplasms Objective response Pharmacology Sulfonamides IMPROVED SURVIVAL MUTATIONS business.industry Melanoma Imidazoles Dabrafenib General Medicine medicine.disease MAPK digestive system diseases medicine.anatomical_structure Cancer research vemurafenib business medicine.drug |
| Zdroj: | EXPERT OPINION ON PHARMACOTHERAPY, 15(5), 589-592. TAYLOR & FRANCIS LTD |
| ISSN: | 1744-7666 1465-6566 |
| DOI: | 10.1517/14656566.2014.881471 |
| Popis: | The clinical development of selective BRAF inhibitors for metastatic BRAF V600 mutant melanoma patients has been a major breakthrough in targeted therapeutics. Objective response rates of approximately 50% have been observed in the Phase III studies of the BRAF inhibitors vemurafenib and dabrafenib. The side effects can be relatively common, including proliferative skin toxicities. The latter range from hyperkeratosis and keratoacanthomas (KAs) to squamous cell carcinomas (SCCs) and new primary melanomas. In addition, case reports on the emergence of gastric/colonic polyps and RAS mutant malignancies have been described during BRAF inhibitor therapy. These events have been attributed to paradoxical activation of the MAPK pathway in BRAF wildtype cells exposed to selective BRAF inhibitors in addition to increased RAS activity. Combined BRAF and MEK inhibition appears to improve clinical outcomes and reduce cutaneous proliferation events as fewer KAs and SCCs have been observed with combination therapy. Next-generation pan-RAF inhibitors ('paradox breakers') and ERK inhibitors may further enhance clinical activity in metastatic BRAF-mutant melanoma patients and mitigate this paradoxical oncogenesis. Further investigation into the potential long-term effects of selective BRAF inhibitors is warranted as expanded use of these agents is expected in patients with BRAF-mutant melanoma and other malignancies. |
| Databáze: | OpenAIRE |
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