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Narrative Review: BRAF Opens the Door for Therapeutic Advances in Melanoma

Keith T. Flaherty, MD
[+] Article, Author, and Disclosure Information

From Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Grant Support: The phase 1 and phase 2 trials of PLX4032 were supported by Plexxikon.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-1207.

Requests for Single Reprints: Keith T. Flaherty, MD, Massachusetts General Hospital, 55 Fruit Street, Yawkey 9E, Boston, MA 02114; e-mail, kflaherty@partners.org.

Current Author Address: Dr. Flaherty: Massachusetts General Hospital, 55 Fruit Street, Yawkey 9E, Boston, MA 02114.

Author Contributions: Conception and design: K.T. Flaherty.

Analysis and interpretation of the data: K.T. Flaherty.

Drafting of the article: K.T. Flaherty.

Critical revision of the article for important intellectual content: K.T. Flaherty.

Final approval of the article: K.T. Flaherty.

Administrative, technical, or logistic support: K.T. Flaherty.

Collection and assembly of data: K.T. Flaherty.

Ann Intern Med. 2010;153(9):587-591. doi:10.7326/0003-4819-153-9-201011020-00008
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Patients with metastatic melanoma have a poor prognosis and limited treatment options. In about one half of analyzed patients with metastatic melanoma, a mutated signal transduction molecule has been identified: v-raf murine sarcoma viral oncogene homolog B1 (BRAF). This molecule is part of an intracellular signaling cascade and may play a role in many different types of cancer. This article provides an overview of the current treatment options for metastatic melanoma and describes the pathophysiology underlying the development of therapies based on inhibition of BRAF. It summarizes findings of phase 1 and phase 2 studies of BRAF inhibitor therapy primarily in patients with metastatic melanoma, who have shown objective response rates of 70% to 80%. However, initial responses have not been sustained, with a median time to relapse of approximately 9 months. Clinicians should be aware of phase 3 trials of these agents and trials combining these therapies with other novel therapies because, at a minimum, BRAF inhibitors seem to be valuable as palliative therapy for metastatic melanoma.


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Role of BRAF in retrovirus-associated sequence signal transduction pathways.

Akt = v-akt murine thymoma viral oncogene homolog 1; BRAF = v-raf murine sarcoma viral oncogene homolog B1; CRAF = v-raf-1 murine leukemia viral oncogene homolog 1; ERK = extracellular signal–regulated kinase; MAPK = mitogen-activated protein kinase; MEK = mitogen-activated protein kinase kinase; NRAS = neuroblastoma retrovirus-associated sequence; PTEN = phosphatase and tensin homolog; mTOR = mammalian target of rapamycin; PI3K = phosphatidylinositol 3-kinase.

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