COX-2 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by BRAF inhibitors
COX-2 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by BRAF inhibitors
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DOI：
10.1016/j.molonc.2013.11.005
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发表时间：
2014-03-01
影响因子：
6.6
通讯作者：
Ribas, Antoni
中科院分区：
文献类型：
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作者：
Escuin-Ordinas, Helena;Atefi, Mohammad;Ribas, Antoni
在接受BRAF抑制剂（BRAFi）治疗的BRAF（V600 E）转移性黑色素瘤患者中，15-30%发生角化棘皮瘤（KA）和皮肤鳞状细胞癌（cuSCC）。这些病变类似于由两阶段DMBA/TPA皮肤致癌方案诱导的小鼠皮肤肿瘤;在该方案中，BRAFi加速肿瘤诱导。由于先前的研究表明环氧合酶2（考克斯-2）是DMBA/TPA肿瘤诱导所必需的，我们假设考克斯-2抑制可能会预防BRAFI加速的皮肤肿瘤。塞来昔布是一种考克斯-2抑制剂，可显著延迟BRAFi抑制剂PLX 7420对肿瘤的加速作用，并使肿瘤数量减少90%。肿瘤基因表达谱分析表明，塞来昔布部分逆转PLX 4720诱导的基因签名。在PDV cuSCC细胞中，vemurafenib（临床批准的BRAFi）增加ERK磷酸化和软琼脂集落形成;塞来昔布大大降低了这两种反应。在临床试验中，曲美替尼，MEK抑制剂（MEKi）增加BRAF（V600 E）E黑色素瘤的BRAFi治疗疗效，并降低BRAFi诱导的KA和cuSCC频率。曲美替尼也减少了维罗非尼诱导的PDV软琼脂菌落，但效果不如塞来昔布。曲美替尼/塞来昔布联合用药比单独使用任一种抑制剂更有效。总之，塞来昔布抑制了BRAFi加速的皮肤肿瘤和软琼脂集落，证明了其作为BRAFi单独治疗或与MEKi联合治疗患者的非黑色素瘤皮肤病变的化学预防剂的测试。(C)2013年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
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) E 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. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.