表皮生长因子受体抑制剂对 PI3K/Akt/mTOR 活性的差异调节：顺铂耐药头颈部鳞状细胞癌中共同靶向 EGFR 和 PI3K 的原理。
Differential modulation of PI3K/Akt/mTOR activity by EGFR inhibitors: A rationale for co-targeting EGFR and PI3K in cisplatin-resistant HNSCC.
机构信息
University of Maryland Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
出版信息
Head Neck. 2024 May;46(5):1126-1135. doi: 10.1002/hed.27718. Epub 2024 Mar 1.
PURPOSE
To find a new strategy to treat cisplatin-resistant head and neck squamous cell carcinoma (HNSCC), we investigated the effects of EGFR inhibitors on the PI3K/Akt/mTOR pathway and determined the efficacy of EGFR inhibitors in combination with PI3K inhibitors to suppress cell proliferation in cisplatin-resistant-HNSCC.
METHODS
The cisplatin-resistant HNSCC cell lines were treated with four FDA approved EGFR inhibitors, which included Gefitinb or Erlotinib alone, or in combination with the pan-PI3K inhibitor, BKM120. Phosphorylation and total protein levels of cells were assessed by Western blot analysis. Cell proliferation was examined by MTS assay. Apoptosis was analyzed by flow cytometry.
RESULTS
Cisplatin-resistant HNSCC cells were also resistant to EGFR inhibitors. However, a combination of EGFR inhibitors with PI3K inhibitor BKM120 dramatically improved the efficacy of EGFR inhibitors to inhibit cell proliferation and induce apoptosis. Furthermore, treatment with EGFR inhibitors differentially affected the phosphorylation of Akt and mTOR, which included partial inhibition, no inhibition, and induction. A combination of EGFR inhibitors and BKM120 completely blocked phosphorylation of EGFR, Akt, and S6K (an mTOR target).
CONCLUSION
Our data provided a rationale for EGFR inhibitors in combination with PI3K inhibitors to treat cisplatin-resistant HNSCC.
目的
为了寻找一种新的策略来治疗顺铂耐药的头颈部鳞状细胞癌（HNSCC），我们研究了 EGFR 抑制剂对 PI3K/Akt/mTOR 通路的影响，并确定了 EGFR 抑制剂与 PI3K 抑制剂联合抑制顺铂耐药-HNSCC 细胞增殖的疗效。
方法
用四种 FDA 批准的 EGFR 抑制剂处理顺铂耐药的 HNSCC 细胞系，包括 Gefitinib 或 Erlotinib 单独使用，或与泛 PI3K 抑制剂 BKM120 联合使用。通过 Western blot 分析评估细胞的磷酸化和总蛋白水平。通过 MTS 分析检测细胞增殖。通过流式细胞术分析细胞凋亡。
结果
顺铂耐药的 HNSCC 细胞对 EGFR 抑制剂也有耐药性。然而，EGFR 抑制剂与 PI3K 抑制剂 BKM120 的联合使用显著提高了 EGFR 抑制剂抑制细胞增殖和诱导细胞凋亡的疗效。此外，EGFR 抑制剂的治疗对 Akt 和 mTOR 的磷酸化有不同的影响，包括部分抑制、无抑制和诱导。EGFR 抑制剂与 BKM120 的联合使用完全阻断了 EGFR、Akt 和 S6K（mTOR 的靶标）的磷酸化。
结论
我们的数据为 EGFR 抑制剂与 PI3K 抑制剂联合治疗顺铂耐药的 HNSCC 提供了一个合理的依据。
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