Identification of Unique MEK-Dependent Genes in GNAQ Mutant Uveal Melanoma Involved in Cell Growth, Tumor Cell Invasion, and MEK Resistance

摘要: Purpose: Metastatic uveal melanoma represents the most common intraocular malignancy with very poor prognosis and no effective treatments. Oncogenic mutations in G-protein α-subunit q 11 have been described about 85% of melanomas confer constitutive activation. Multiple signaling pathways are induced as a consequence GNAQ/11 activation, which include MEK/ERK kinase cascade. We analyzed transcriptional profile cell lines treated mitogen-activated protein (MAP)/extracellular signal–regulated (ERK) (MEK) inhibitor to identify gene targets activated GNAQ evaluate biologic importance these genes melanoma. Experimental Design: conducted microarray analysis MEK selumetinib. For comparison, we used cells carrying BRAF V600E without either mutation. Changes expression selected were then confirmed by quantitative real-time PCR immunoblotting. Results: found that mutant MEK-dependent output identified unique set downregulated inhibition, including RNA helicase DDX21 cyclin-dependent regulator CDK5R1 whereas Jun was induced. provide evidence involved proliferation, tumor invasion, drug resistance, respectively. Furthermore, show selumetinib treatment regulates tissues patients metastatic Conclusions: Our findings define subset transcriptionally regulated new insights into understanding effect inhibition this disease. Clin Cancer Res; 18(13); 3552–61. ©2012 AACR .