COX-2 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by BRAF inhibitors.
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.
['Escuin-Ordinas|Helena|H|', 'Atefi|Mohammad|M|', 'Fu|Yong|Y|', 'Cass|Ashley|A|', 'Ng|Charles|C|', 'Huang|Rong Rong|RR|', 'Yashar|Sharona|S|', 'Comin-Anduix|Begonya|B|', 'Avramis|Earl|E|', 'Cochran|Alistair J|AJ|', 'Marais|Richard|R|', 'Lo|Roger S|RS|', 'Graeber|Thomas G|TG|', 'Herschman|Harvey R|HR|', 'Ribas|Antoni|A|']
D000818:Animals D002294:Carcinoma, Squamous Cell D000068579:Celecoxib D051546:Cyclooxygenase 2 D052246:Cyclooxygenase 2 Inhibitors D005260:Female D015972:Gene Expression Regulation, Neoplastic D006801:Humans D007211:Indoles D007636:Keratoacanthoma D008545:Melanoma D051379:Mice D047428:Protein Kinase Inhibitors D048493:Proto-Oncogene Proteins B-raf D011720:Pyrazoles D011728:Pyridones D011744:Pyrimidinones D012878:Skin Neoplasms D013449:Sulfonamides D000077484:Vemurafenib
COX-2 Squamous cell carcinomas celecoxib vemurafenib trametinib