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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.

SUBMITTER: Escuin-Ordinas H

PROVIDER: S-EPMC3943738 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Importance:Solid organ transplant recipients (SOTRs) have a 100-fold increased risk of squamous cell carcinoma (SCC), and they may develop more aggressive SCCs compared with immunocompetent individuals. Objective:To compare outcomes associated with aggressive behavior of SCC in SOTRs and high-risk immunocompetent patients. Design, Setting, and Participants:A retrospective cohort study of 58 SOTRs and 40 immunocompetent patients evaluated at the Yale Transplant Dermatology Clinic in New Haven, Connecticut, who had at least 1 SCC confirmed histopathologically between January 1, 2008, and December 31, 2015. Cumulative follow-up time for this study was 369 patient-years. Exposure:Immunosuppressive medication regimen for SOTRs. Main Outcomes and Measures:The primary outcome measure was tumor depth of SCC. Secondary outcome measures that reflected tumor aggressiveness included perineural invasion, regional metastases, nodal metastases, disease-specific death, and overall death. Results:Of the 58 SOTR study participants, 14 were women and 44 were men; the mean (SD) age was 61.3 (8.4) years. Of the 40 immunocompetent study participants, 16 were women and 24 were men; the mean (SD) age was 69.8 (10.9) years, resulting in a statistically significant difference from the SOTR group. The mean (SD) number of years that SOTRs were immunosuppressed was 14.6 (9.2) years (range, 2-37 years). The SOTR and immunocompetent groups were statistically comparable regarding race and sex, patient care, follow-up time, numbers of skin lesions, and field cancerization and chemopreventive therapies. The SOTR group had a significantly higher annual frequency of visits (mean [SD], 4 [2] vs 3 [2] office visits per patient per year, P?=?.02) and annual biopsy rates (mean [SD], 6 [4] vs 5 [3] biopsies per patient per year, P?=?.04). The SOTRs developed SCCs that did not appear to be significantly more aggressive than those found in the immunocompetent control group. These SOTRs also did not develop significantly thicker tumors than the immunocompetent control group (median [IQR] tumor depth, 1.30 [0.90-1.60] mm in 35 SOTRs vs 1.22 [1.10-1.60] mm in 20 immunocompetent patients). Conclusions and Relevance:The increased risk and the potential for aggressive behavior of SCCs in SOTRs may be successfully managed at a level comparable to that in high-risk immunocompetent individuals through close adherence to current dermatologic surveillance recommendations and a marginally lower threshold for biopsy of suspicious lesions for SOTRs.

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

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