COX-2 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by BRAF inhibitors.
Authors
Escuin-Ordinas, HAtefi, 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
Affiliation
Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA),Los Angeles, CA, USAIssue Date
2013-12-01
Metadata
Show full item recordAbstract
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 OncolJournal
Molecular OncologyDOI
10.1016/j.molonc.2013.11.005PubMed ID
24345644Type
ArticleLanguage
enISSN
1878-0261ae974a485f413a2113503eed53cd6c53
10.1016/j.molonc.2013.11.005