Niehr Franziska, Weichert Wilko, Stenzinger Albrecht, Budach Volker, Tinhofer Ingeborg
Translational Radiooncology Laboratory, Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany.
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, Partner Site Berlin, Berlin, Germany.
J Transl Med. 2015 Apr 1;13:106. doi: 10.1186/s12967-015-0456-6.
The mammalian target of rapamycin (mTOR) signaling pathway plays a pivotal role in numerous cellular processes involving growth, proliferation and survival. The purpose of this study was to investigate the anti-tumoral effect of the mTOR inhibitor (mTORi) CCI-779 in HNSCC cell lines and its potency in cisplatin- and cetuximab-resistant cells.
A panel of 10 HNSCC cell lines with differences in TP53 mutational status and basal cisplatin sensitivity and two isogenic models of acquired resistance to cisplatin and cetuximab, respectively were studied. Cell survival after treatment with CCI-779, cisplatin and cetuximab alone or in combination was determined by MTT assays. Potential predictive biomarkers for tumor cell sensitivity to CCI-779 were evaluated.
We observed considerable heterogeneity in sensitivity of HNSCC cell lines to CCI-779 monotherapy. Sensitivity was observed in TP53 mutated as well as wild-type cell lines. Total and p-EGFR expression levels but not the basal activity of the mTOR and MAPK signaling pathways were correlated with sensitivity to CCI-779. Resistant cells with increased EGFR activation could be sensitized by the combination of CCI-779 with cetuximab. Interestingly, cell lines with acquired resistance to cisplatin displayed a higher sensitivity to CCI-779 whereas cetuximab-resistant cells were less sensitive to the drug, but could be sensitized to CCI-779 by EGFR blockade.
Activity of CCI-779 in HNSCC cells harboring TP53 mutations and displaying a phenotype of cisplatin resistance suggests its clinical potential even in patients with dismal outcome after current standard treatment. Cetuximab/mTORi combinations might be useful for treatment of tumors with high expression of EGFR/p-EGFR and/or acquired cetuximab resistance. This combinatorial treatment modality needs further evaluation in future translational and clinical studies.
雷帕霉素哺乳动物靶点（mTOR）信号通路在涉及生长、增殖和存活的众多细胞过程中起关键作用。本研究旨在探讨mTOR抑制剂（mTORi）CCI-779对头颈部鳞状细胞癌（HNSCC）细胞系的抗肿瘤作用及其对顺铂和西妥昔单抗耐药细胞的效力。
研究了一组10种HNSCC细胞系，这些细胞系在TP53突变状态和基础顺铂敏感性方面存在差异，以及分别对顺铂和西妥昔单抗获得性耐药的两个同基因模型。通过MTT法测定单独或联合使用CCI-779、顺铂和西妥昔单抗处理后的细胞存活率。评估了肿瘤细胞对CCI-779敏感性的潜在预测生物标志物。
我们观察到HNSCC细胞系对CCI-779单药治疗的敏感性存在相当大的异质性。在TP53突变以及野生型细胞系中均观察到敏感性。总EGFR和磷酸化EGFR（p-EGFR）表达水平，而非mTOR和丝裂原活化蛋白激酶（MAPK）信号通路的基础活性，与对CCI-779的敏感性相关。EGFR激活增加的耐药细胞可通过CCI-779与西妥昔单抗联合而致敏。有趣的是，对顺铂获得性耐药的细胞系对CCI-779表现出更高的敏感性，而西妥昔单抗耐药细胞对该药物敏感性较低，但可通过EGFR阻断使其对CCI-779致敏。
CCI-779在携带TP53突变并表现出顺铂耐药表型的HNSCC细胞中的活性表明，即使在当前标准治疗后预后不佳的患者中，它也具有临床潜力。西妥昔单抗/mTORi联合可能对EGFR/p-EGFR高表达和/或获得性西妥昔单抗耐药的肿瘤治疗有用。这种联合治疗方式需要在未来的转化和临床研究中进一步评估。
