MEK Inhibition Overcomes Cisplatin Resistance Conferred by SOS/MAPK Pathway Activation in Squamous Cell Carcinoma
MEK Inhibition Overcomes Cisplatin Resistance Conferred by SOS/MAPK Pathway Activation in Squamous Cell Carcinoma
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DOI：
10.1158/1535-7163.mct-15-0062
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发表时间：
2015-07-01
影响因子：
5.7
通讯作者：
Goh, Boon Cher
中科院分区：
文献类型：
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作者：
Kong, Li Ren;Chua, Kian Ngiap;Goh, Boon Cher
对鳞状细胞癌(SCC)的基因组分析还没有得出有效的策略来对抗通路激活来改善治疗。铂为主的化疗仍然是不同组织类型的鳞癌的主要治疗方法，无论是作为单一药物还是与其他化疗药物或放疗联合使用，但不可避免地会出现耐药性，这限制了治疗反应的持续时间。为了阐明顺铂耐药的机制，我们比较了药物对顺铂敏感和耐药的SCC细胞基因和蛋白表达的影响，并鉴定了MAPK-ERK通路在耐药细胞中的上调和激活。ERK诱导的抗性上游可能由Seven less Son(SOS)激活，下游通过Bim降解介导。临床上，同时接受放化疗的局部晚期头颈部鳞状细胞癌患者中，p-ERK表达升高与较短的无病生存期有关。抑制MEK/ERK，而不是抑制EGFR或RAF，在体外增加了顺铂的敏感性，并在体内证明了有效性和耐受性。总之，这些发现表明，抑制激活的SOS-MAPK-ERK通路可能会增强患者对顺铂治疗的反应。(C)2015年AACR。
Genomic analyses of squamous cell carcinoma (SCC) have yet to yield significant strategies against pathway activation to improve treatment. Platinum-based chemotherapy remains the mainstay of treatment for SCC of different histotypes either as a single-agent or alongside other chemotherapeutic drugs or radiotherapy; however, resistance inevitably emerges, which limits the duration of treatment response. To elucidate mechanisms that mediate resistance to cisplatin, we compared drug-induced perturbations to gene and protein expression between cisplatin sensitive and -resistant SCC cells, and identified MAPK-ERK pathway upregulation and activation in drug-resistant cells. ERK-induced resistance appeared to be activated by Son of Sevenless (SOS) upstream, and mediated through Bim degradation downstream. Clinically, elevated p-ERK expression was associated with shorter disease-free survival in patients with locally advanced head and neck SCC treated with concurrent chemoradiation. Inhibition of MEK/ERK, but not that of EGFR or RAF, augmented cisplatin sensitivity in vitro and demonstrated efficacy and tolerability in vivo. Collectively, these findings suggest that inhibition of the activated SOS-MAPK-ERK pathway may augment patient responses to cisplatin treatment. (C)2015 AACR.