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    COX-2 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by BRAF inhibitors.

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    Authors
    Escuin-Ordinas, H
    Atefi, M
    Fu, Y
    Cass, A
    Ng, C
    Huang, R
    Yashar, S
    Comin-Anduix, B
    Avramis, E
    Cochran, A
    Marais, Richard
    Lo, R
    Graeber, T
    Herschman, H
    Ribas, A
    Show allShow less
    Affiliation
    Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA),Los Angeles, CA, USA
    Issue Date
    2013-12-01
    
    Metadata
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    Abstract
    Keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cuSCCs) develop in 15-30% of patients with BRAF(V600E) metastatic melanoma treated with BRAF inhibitors (BRAFi). These lesions resemble mouse skin tumors induced by the two-stage DMBA/TPA skin carcinogenesis protocol; in this protocol BRAFi accelerates tumor induction. Since prior studies demonstrated cyclooxygenase 2 (COX-2) is necessary for DMBA/TPA tumor induction, we hypothesized that COX-2 inhibition might prevent BRAFi-accelerated skin tumors. Celecoxib, a COX-2 inhibitor, significantly delayed tumor acceleration by the BRAFi inhibitor PLX7420 and decreased tumor number by 90%. Tumor gene expression profiling demonstrated that celecoxib partially reversed the PLX4720-induced gene signature. In PDV cuSCC cells, vemurafenib (a clinically approved BRAFi) increased ERK phosphorylation and soft agar colony formation; both responses were greatly decreased by celecoxib. In clinical trials trametinib, a MEK inhibitor (MEKi) increases BRAFi therapy efficacy in BRAF(V600E) melanomas and reduces BRAFi-induced KA and cuSCC frequency. Trametinib also reduced vemurafenib-induced PDV soft agar colonies, but less efficiently than celecoxib. The trametinb/celecoxib combination was more effective than either inhibitor alone. In conclusion, celecoxib suppressed both BRAFi-accelerated skin tumors and soft-agar colonies, warranting its testing as a chemopreventive agent for non-melanoma skin lesions in patients treated with BRAFi alone or in combination with MEKi.
    Citation
    COX-2 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by BRAF inhibitors. 2013: Mol Oncol
    Journal
    Molecular Oncology
    URI
    http://hdl.handle.net/10541/312677
    DOI
    10.1016/j.molonc.2013.11.005
    PubMed ID
    24345644
    Type
    Article
    Language
    en
    ISSN
    1878-0261
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.molonc.2013.11.005
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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