Hyperactivation of MEK-ERK1 2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells

• Published in: Oncogene Vol. 30; no. 3; pp. 366 - 371
• Main Authors: Kaplan, F M, Shao, Y, Mayberry, M M, Aplin, A E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.01.2011; Nature Publishing Group
• Subjects: 631/154/436/2388; 631/208/68; 692/699/67/1813/1634; Ageing, cell death; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Cell Biology; Cell cycle; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular signal transduction; Dermatology; Drug therapy; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Genes, ras; Genetic aspects; Genotype & phenotype; Health aspects; Human Genetics; Humans; Indoles - pharmacology; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Melanoma; Melanoma - enzymology; Melanoma - pathology; Molecular and cellular biology; Mutation; Oncology; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Ras genes; Risk factors; short-communication; Signal Transduction; Skin cancer; Sulfonamides - pharmacology; Tumors of the skin and soft tissue. Premalignant lesions; United States; apoptosis; B-RAF; N-RAS; PLX4720; Extracellular signal-regulated protein kinase; Enzyme; Malignant tumor; Carcinogenesis; Resistance; C-Onc gene; Malignant melanoma; Inhibitor; Mutation; Protooncogene; Cancer; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.408

Activating mutations in B-RAF and N-RAS occur in ∼60 and ∼15% of melanomas, respectively. The most common mutation in B-RAF is V600E, which activates B-RAF and the downstream MEK–ERK1/2 pathway. Thus, B-RAF V600E is a viable therapeutic target. PLX4720 is a selective inhibitor of mutant B-RAF and its analog, PLX4032, is currently undergoing clinical trials in melanoma. However, the effects of PLX4720 across the genotypic spectrum in melanoma remain unclear. Here, we describe that PLX4720 treatment rapidly induces hyperactivation of the MEK–ERK1/2 pathway in mutant N-RAS melanoma cells. Furthermore, we demonstrate that C-RAF is the major RAF isoform involved in this process. Importantly, PLX4720-induced hyperactivation of the MEK–ERK1/2 pathway promotes resistance to apoptosis in both non-invasive and invasive mutant N-RAS melanoma cells but does not enhance cell cycle properties. These findings underscore the need to genotypically stratify melanoma patients before enrollment on a mutant B-RAF inhibitor trial.