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

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.

• Authors: Helena Escuin-Ordinas, Mohammad Atefi, Yong Fu, Ashley Cass, Charles Ng, Rong Rong Huang, Sharona Yashar, Begonya Comin-Anduix, Earl Avramis, Alistair J Cochran, Richard Marais, Roger S Lo, Thomas G Graeber, Harvey R Herschman, Antoni Ribas
• Journal: Molecular oncology (Mol Oncol) Vol. 8 Issue 2 Pg. 250-60 (Mar 2014) ISSN: 1878-0261 [Electronic] United States
• PMID: 24345644 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Federation of European Biochemical Societies. All rights reserved.

Chemical References

• Cyclooxygenase 2 Inhibitors
• Indoles
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridones
• Pyrimidinones
• Sulfonamides
• Vemurafenib
• trametinib
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Braf protein, mouse
• Proto-Oncogene Proteins B-raf
• Celecoxib

Topics

• Animals
• Carcinoma, Squamous Cell (drug therapy, genetics, metabolism, pathology)
• Celecoxib
• Cyclooxygenase 2 (genetics, metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Humans
• Indoles (pharmacology)
• Keratoacanthoma (diet therapy, genetics, metabolism, pathology)
• Melanoma (drug therapy, genetics, metabolism, pathology)
• Mice
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics, metabolism)
• Pyrazoles (pharmacology)
• Pyridones (pharmacology)
• Pyrimidinones (pharmacology)
• Skin Neoplasms (drug therapy, genetics, metabolism, pathology)
• Sulfonamides (pharmacology)
• Vemurafenib