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Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and
even fewer experience durable survival benefit. These poor results may come from treating
all melanomas as though they are biologically homogeneous. Recently, it has been shown
that targeting specific activated tyrosine kinases (oncogenes) can have striking clinical
benefits in patients with melanoma. In 2002, a V600E mutation of the BRAF serine/
threonine kinase was described as present in more than 50% of all melanomas. The
mutation appeared to confer a dependency by the melanoma cancer cell on activated
signaling through mitogen-activated protein kinase pathway. The frequency and focality of
this mutation (>95% of all BRAF mutations being at V600 position) suggested its importance
in melanoma pathophysiology and potential as a target for therapy. The recent results
of a phase 1 study with PLX4032/RG7204, a small molecule RAF inhibitor, confirm this
hypothesis. Mucosal and acral-lentiginous melanomas, comprising 3% of all melanomas,
frequently harbor activating mutations of c-kit and drugs targeting this mutation seem to
confer similar benefits for these types of tumors. Here we provide an overview of the
targeted therapy development in melanoma with emphasis on BRAF inhibition because of
its prevalence and possibility of transforming the care of many melanoma patients.
Semin Cutan Med Surg 29:196-201 © 2010 Elsevier Inc. All rights reserved.
Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and
even fewer experience durable survival benefit. These poor results may come from treating
all melanomas as though they are biologically homogeneous. Recently, it has been shown
that targeting specific activated tyrosine kinases (oncogenes) can have striking clinical
benefits in patients with melanoma. In 2002, a V600E mutation of the BRAF serine/
threonine kinase was described as present in more than 50% of all melanomas. The
mutation appeared to confer a dependency by the melanoma cancer cell on activated
signaling through mitogen-activated protein kinase pathway. The frequency and focality of
this mutation (>95% of all BRAF mutations being at V600 position) suggested its importance
in melanoma pathophysiology and potential as a target for therapy. The recent results
of a phase 1 study with PLX4032/RG7204, a small molecule RAF inhibitor, confirm this
hypothesis. Mucosal and acral-lentiginous melanomas, comprising 3% of all melanomas,
frequently harbor activating mutations of c-kit and drugs targeting this mutation seem to
confer similar benefits for these types of tumors. Here we provide an overview of the
targeted therapy development in melanoma with emphasis on BRAF inhibition because of
its prevalence and possibility of transforming the care of many melanoma patients.
Semin Cutan Med Surg 29:196-201 © 2010 Elsevier Inc. All rights reserved.