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

详细信息    查看全文

• 作者：Helena Escuin-Ordinas^a ; Mohammad Atefi^a ; Yong Fu^b ; Ashley Cass^c ; Charles Ng^a ; Rong Rong Huang^d ; Sharona Yashar^d ; Begonya Comin-Anduix^e ; ^g ; Earl Avramis^e ; Alistair J. Cochran^d ; ^g ; Richard Marais^h ; Roger S. Lo^f ; ^g ; Thomas G. Graeber^c ; ^g ; Harvey R. Herschman^b ; ^c ; ^g ; ^{hherschman@mednet.ucla.edu" class="auth_mail} ; Antoni Ribas^a ; ^c ; ^e ; ^g ; ^{aribas@mednet.ucla.edu" class="auth_mail}
• 关键词：Squamous cell carcinomas ; COX-2 ; celecoxib ; vemurafenib ; trametinib
• 刊名：Molecular Oncology
• 出版年：March, 2014
• 年：2014
• 卷：8
• 期：2
• 页码：250-260
• 全文大小：1867 K

文摘

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.