Identification of unique MEK-dependent genes in GNAQ mutant uveal melanoma involved in cell growth, tumor cell invasion, and MEK resistance Journal Article

Authors: Ambrosini, G.; Pratilas, C. A.; Qin, L. X.; Tadi, M.; Surriga, O.; Carvajal, R. D.; Schwartz, G. K.
Article Title: Identification of unique MEK-dependent genes in GNAQ mutant uveal melanoma involved in cell growth, tumor cell invasion, and MEK resistance
Abstract: Purpose: Metastatic uveal melanoma represents the most common intraocular malignancy with very poor prognosis and no effective treatments. Oncogenic mutations in the G-protein α-subunit q and 11 have been described in about 85% of uveal melanomas and confer constitutive activation. Multiple signaling pathways are induced as a consequence of GNAQ/11 activation, which include the MEK/ERK kinase cascade.Weanalyzed the transcriptional profile of cell lines treated with a mitogen-activated protein (MAP)/ extracellular signal-regulated (ERK) kinase (MEK) inhibitor to identify gene targets of activated GNAQ and to evaluate the biologic importance of these genes in uveal melanoma. Experimental Design: We conducted microarray analysis of uveal melanoma cell lines with GNAQ mutations treated with the MEK inhibitor selumetinib. For comparison, we used cells carrying BRAFV600E and cells without either mutation. Changes in the expression of selected genes were then confirmed by quantitative real-time PCR and immunoblotting. Results: We found that GNAQ mutant cells have a MEK-dependent transcriptional output and identified a unique set of genes that are downregulated byMEKinhibition, including theRNA helicase DDX21 and the cyclin-dependent kinase regulator CDK5R1 whereas Jun was induced. We provide evidence that these genes are involved in cell proliferation, tumor cell invasion, and drug resistance, respectively. Furthermore, we show that selumetinib treatment regulates the expression of these genes in tumor tissues of patients with metastatic GNAQ/11 mutant uveal melanoma. Conclusions: Our findings define a subset of transcriptionally regulated genes by selumetinib in GNAQ mutant cells and provide new insights into understanding the biologic effect of MEK inhibition in this disease. ©2012 AACR.
Keywords: mitogen activated protein kinase; controlled study; human tissue; unclassified drug; human cell; mutation, missense; antineoplastic agents; cell proliferation; cell survival; melanoma; gene expression profiling; map kinase signaling system; transcription, genetic; antineoplastic activity; cancer cell culture; drug resistance; drug resistance, neoplasm; cell line, tumor; mutational analysis; cancer invasion; gene expression regulation; cancer inhibition; gene expression regulation, neoplastic; transcription regulation; microarray analysis; oligonucleotide array sequence analysis; immunoblotting; cell movement; down regulation; real time polymerase chain reaction; tumor growth; uvea melanoma; uveal neoplasms; clinical trials, phase ii as topic; glutamic acid; rna helicase; b raf kinase; benzimidazoles; proto-oncogene proteins b-raf; cell mutant; valine; genetic selection; genetic identification; jnk mitogen-activated protein kinases; map kinase kinase kinases; selumetinib; guanine nucleotide binding protein alpha subunit; cyclin dependent kinase 5; protein c jun; protein gnaq; protein cdk5r1; protein ddx21; gtp-binding protein alpha subunits
Journal Title: Clinical Cancer Research
Volume: 18
Issue: 13
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2012-07-01
Start Page: 3552
End Page: 3561
Language: English
DOI: 10.1158/1078-0432.ccr-11-3086
PROVIDER: scopus
PUBMED: 22550165
PMCID: PMC3433236
Notes: --- - "Export Date: 1 August 2012" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Gary Schwartz
    358 Schwartz
  2. Richard D Carvajal
    133 Carvajal
  3. Li-Xuan Qin
    114 Qin
  4. Madhavi Tadi
    11 Tadi