Mechanism of BRAF Inhibitor Resistance Elucidated

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(ChemotherapyAdvisor) – Alternative clinical strategies have the potential to overcome the underlying acquired B-RAF inhibitor resistance that can hamper long-term therapeutic success in melanoma, an article published in Nature Communications online March 6 has found.

To date, five mechanisms of BRAF inhibitor resistance have been detected in patients with melanoma, accounting for about 60% to 70% of patients; however, 30% to 40% relapse by as yet unknown mechanisms.

“In cell lines, V600EB-RAF overexpression and knockdown conferred B-RAF inhibitor resistance and sensitivity, respectively,” the investigators wrote. They examined samples of 20 patients with metastatic melanoma, including normal tissue; tissue prior to treatment with the B-RAF inhibitor, vemurafenib; and a sample of tissue in which the cancer had responded earlier but subsequently became resistant.

Higher doses of vemurafenib were found to down-regulate phosho-extracellular signal-regulated kinase and re-sensitize melanoma cells to B-RAF inhibitor. In 5 of 20 patients (20%) treated with B-RAF inhibitor, V600EB-RAF copy-number gain was demonstrated as a mechanism of acquired B-RAF inhibitor resistance.

Approximately 50% of patients with metastatic melanoma (4,000 annually) have the BRAF mutation and can be treated with oral vemurafenib (Zelboraf), approved August 2011 by the U.S. Food and Drug Administration. Many other common human cancers, including colon, thyroid and lung, also harbor BRAF-mutated subsets, the investigators said.

These findings may lead to vemurafenib being administered in combination with inhibitors of other cell signaling pathways to try to prevent resistance.

Abstract

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