Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Institute of Molecular and Cell Biology, A*STAR, Singapore.
Mol Cancer Ther. 2015 Jul;14(7):1750-60. doi: 10.1158/1535-7163.MCT-15-0062. Epub 2015 May 4.
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.
对鳞状细胞癌（SCC）的基因组分析尚未产生针对通路激活的重大策略来改善治疗效果。铂类化疗仍然是不同组织类型 SCC 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射治疗联合使用；然而，耐药性不可避免地出现，限制了治疗反应的持续时间。为了阐明介导顺铂耐药的机制，我们比较了顺铂敏感和耐药 SCC 细胞中药物诱导的基因和蛋白质表达变化，并在耐药细胞中发现 MAPK-ERK 通路的上调和激活。ERK 诱导的耐药性似乎通过 Son of Sevenless (SOS) 上游激活，并通过下游 Bim 降解介导。临床上，接受同期放化疗的局部晚期头颈部 SCC 患者中，p-ERK 表达升高与无病生存期较短相关。体外抑制 MEK/ERK 而不是 EGFR 或 RAF，可增强顺铂的敏感性，并在体内显示出疗效和耐受性。总之，这些发现表明抑制激活的 SOS-MAPK-ERK 通路可能增强患者对顺铂治疗的反应。
