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Mol Oncol. 2014 Mar;8(2):250-60. doi: 10.1016/j.molonc.2013.11.005. Epub 2013 Dec 1.

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

Author information

1
Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
2
Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
3
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
4
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
5
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.
6
Department of Surgery (Division of Surgical-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
7
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.
8
The Paterson Institute, Manchester, UK.
9
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.
10
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.
11
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.
12
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.

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.

KEYWORDS:

COX-2; Squamous cell carcinomas; celecoxib; trametinib; vemurafenib

PMID:
24345644
PMCID:
PMC3943738
DOI:
10.1016/j.molonc.2013.11.005
[Indexed for MEDLINE]
Free PMC Article

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