Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy
Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy
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DOI：
10.1038/sj.bjc.6603656
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发表时间：
2007-03-26
影响因子：
8.8
通讯作者：
Hidalgo, M.
中科院分区：
文献类型：
--
作者：
Jimeno, A.;Kulesza, P.;Hidalgo, M.
表皮生长因子受体 (EGFR) 是头颈部鳞状细胞癌 (SCC) 的有效靶点。然而，大多数患者对该药物没有反应或产生耐药性。哺乳动物雷帕霉素靶蛋白 (mTOR) 参与头颈部鳞状细胞癌 (SCCHN) 的发病机制。本研究旨在确定靶向 mTOR 与 EGFR 联合治疗 SCC 是否有效，并开发早期药效标记物。将两种 SCC 细胞系（一种对 EGFR 抑制剂具有耐药性（HEP2）和一种对 EGFR 抑制剂具有中等敏感性（底特律 562））进行体内异种移植，并用 mTOR 抑制剂（替西罗莫司）、EGFR 抑制剂（厄洛替尼）或两者的组合进行处理。坦罗莫司在两种细胞系中均比厄洛替尼表现出更优异的生长抑制作用。联合治疗在底特律 562 细胞系中产生了协同抗肿瘤作用。使用磷酸 MAPK、Phospho-P70 和 Ki67 作为终点，在治疗后早期对细针抽吸 (FNA) 活检中的药效学效果进行免疫组织化学评估，结果表明联合治疗的底特律 562 肿瘤中的通路被破坏，这是唯一出现回归的组。总之，mTOR 抑制剂在 EGFR 耐药 SCC 细胞系中显示出抗肿瘤活性。显着的抗肿瘤作用与双通路抑制相关，这是通过早期 FNA 活检检测到的。
The epidermal growth factor receptor ( EGFR) is a validated target in squamous cell carcinoma (SCC) of the head and neck. Most patients, however, do not respond or develop resistance to this agent. Mammalian target of rapamycin (mTOR) is involved in the pathogenesis of SCC of the head and neck (SCCHN). This study aimed to determine if targeting mTOR in combination with EGFR is effective in SCC, and to develop early pharmacodynamic markers of efficacy. Two SCC cell lines, one resistant (HEP2) and one of intermediate susceptibility (Detroit 562) to EGFR inhibitors, were xenografted in vivo and treated with an mTOR inhibitor (temsirolimus), an EGFR inhibitor (erlotinib) or a combination of both. Temsirolimus exerted superior growth arrest in both cell lines than erlotinib. The combined treatment resulted in synergistic antitumor effects in the Detroit 562 cell line. Immunohistochemical assessment of pharmacodynamic effects in fine-needle aspiration (FNA) biopsies early after treatment using phospho MAPK, Phospho-P70 and Ki67 as end points demonstrated pathway abrogation in the Detroit 562 tumours treated with the combination, the only group where regressions were seen. In conclusion, an mTOR inhibitor showed antitumor activity in EGFR-resistant SCC cell lines. Marked antitumor effects were associated with dual pathway inhibition, which were detected by early FNA biopsies.