B-RAF Inhibitors: An Evolving Role in the Therapy of Malignant Melanoma

Abstract

Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and even fewer experience durable survival benefit. These poor results come from treating melanoma as a single homogeneous disease. Recently, it has been shown that targeting activated tyrosine kinases (oncogenes) can mediate striking clinical benefits in several cancers. In 2002, a mutation at the V600E amino acid of the BRAF serine/threonine kinase was described as present in over 50% of melanomas. The mutation appeared to confer a dependency by the melanoma cancer cell on its activation of the MAP kinase pathway. The frequency and specificity of this mutation (95% at V600E of BRAF) suggests that it may be a potential target for therapy, and recent results with one inhibitor, PLX4032/RG7204, bare this out. This review updates the status of BRAF inhibitors in melanoma and what may be on the horizon.

Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system

“…42 Patients with tumors carrying these actionable mutations have been treated effectively with appropriate medicines including molecular targeted therapy. In meningiomas, mutations in SMO and AKT1 may be predictive biomarkers of some molecular targeted drugs such as Hedgehog inhibitors and AKT inhibitors.…”

Modulation of l-α-Lysophosphatidylinositol/GPR55 Mitogen-activated Protein Kinase (MAPK) Signaling by Cannabinoids

“…Importantly, inherited and acquired mutations, such as V600E, in B-Raf are associated with various diseases of which most are cancers (28). Therefore, B-Raf inhibitors have been developed as anti-cancer therapeutics.…”

Zastosowanie wemurafenibu u chorych na uogólnionego czerniaka z obecnością mutacji w genie BRAF — wybrane przypadki kliniczne

“…Około 74-90% wszystkich mutacji w genie BRAF dotyczy mutacji punktowej typu zmiany sensu spowodowanej substytucją waliny (V) przez kwas glutaminowy (E) w pozycji 600 egzonu 15 (p.V600E), a około 5-29% dotyczy mutacji V600K, gdzie dochodzi do substytucji waliny (V) przez lizynę (K) [9][10][11][12][13]. Mutacja prowadzi do wielokrotnego zwiększenia aktywności kinazy BRAF, czego konsekwencją jest stymulacja sygnałów ERK, proliferacja komórek i przyrost masy guza [11,14]. Informacje te stały się podstawą do poszukiwań leku hamującego kinazę serynowo-treoninową BRAF.…”