title: 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.affiliation: Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Helena
authors.initials: H
authors.lastname: Escuin-Ordinas
authors.affiliation: Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Atefi
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Cass
authors.affiliation: Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Ng
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Rong Rong
authors.initials: RR
authors.lastname: Huang
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Sharona
authors.initials: S
authors.lastname: Yashar
authors.affiliation: Department of Surgery (Division of Surgical-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Begonya
authors.initials: B
authors.lastname: Comin-Anduix
authors.affiliation: Department of Surgery (Division of Surgical-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Earl
authors.initials: E
authors.lastname: Avramis
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Cochran
authors.affiliation: The Paterson Institute, Manchester, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.affiliation: Department of Medicine (Division of Dermatology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. Electronic address: hherschman@mednet.ucla.edu.
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Herschman
authors.affiliation: Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Department of Surgery (Division of Surgical-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. Electronic address: aribas@mednet.ucla.edu.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007636:Keratoacanthoma / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D000068579:Celecoxib
keywords: COX-2; Squamous cell carcinomas; celecoxib; trametinib; vemurafenib