In Vitro and In Vivo Synergistic Antitumor Activity of the Combination of BKM120 and Erlotinib in Head and Neck Cancer: Mechanism of Apoptosis and Resistance
In Vitro and In Vivo Synergistic Antitumor Activity of the Combination of BKM120 and Erlotinib in Head and Neck Cancer: Mechanism of Apoptosis and Resistance
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DOI：
10.1158/1535-7163.mct-16-0683
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发表时间：
2017-04-01
影响因子：
5.7
通讯作者：
Amin, A. R. M. Ruhul
中科院分区：
文献类型：
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作者：
Anisuzzaman, Abu Syed Md;Haque, Abedul;Amin, A. R. M. Ruhul
我们之前报道过，EGFR 靶向抑制剂厄洛替尼可诱导头颈鳞状细胞癌 (SCCHN) 细胞系 G1 期阻滞，但不会诱导显着的细胞凋亡。大规模基因组研究表明，>50% 的 SCCHN 病例有 PI3K 通路激活。本研究探讨了 EGFR 和 PI3K 的共靶向是否具有协同抗肿瘤作用和诱导细胞凋亡的作用。我们在一组 SCCHN 细胞系和 SCCHN 异种移植模型中分别检测了厄洛替尼和 BKM120 单独和联合靶向 EGFR 和 PI3K 所导致的生长抑制、细胞凋亡和信号通路调节。在一组 12 个细胞系中，使用厄洛替尼单一靶向 EGFR 或使用 BKM120 单一靶向 PI3K 可抑制细胞生长，但不会诱导显着的细胞凋亡。 EGFR 和 PI3K 的共靶向协同抑制 SCCHN 细胞系和异种移植肿瘤的生长，但诱导不同程度的细胞凋亡；有些细胞系高度敏感，有些则具有抵抗力。机制研究表明，该组合可抑制凋亡敏感细胞系中的 mTORC1（S6 和 4EBP1）通路的两个轴，并抑制 Bcl-2、Bcl-xL 和 Mcl-1 的翻译，但无法抑制凋亡抗性细胞系中的 p-4EBP1、Bcl-2、Bcl-xL 和 Mcl-1。 siRNA 介导的 eIF4E 敲低可抑制 Bcl-2 和 Mcl-1 并使该细胞系对细胞凋亡敏感。我们的结果强烈表明，EGFR 和 PI3K 的共靶向具有协同作用，并通过抑制 AKT-mTOR 通路的两个轴和抗凋亡 Bcl-2 蛋白的翻译调节来诱导 SCCHN 细胞系凋亡。这些发现可能会指导使用这种药物组合的临床试验的开展。 (C)2017 AACR。
We previously reported that the EGFR-targeted inhibitor erlotinib induces G1 arrest of squamous cell carcinoma of the head and neck (SCCHN) cell lines without inducing significant apoptosis. Large-scale genomic studies suggest that >50% of SCCHN cases have activation of PI3K pathways. This study investigated whether cotargeting of EGFR and PI3K has synergistic antitumor effects and apoptosis induction. We examined growth suppression, apoptosis, and signaling pathway modulation resulting from single and combined targeting of EGFR and PI3K with erlotinib and BKM120, respectively, in a panel of SCCHN cell lines and a xenograft model of SCCHN. In a panel of 12 cell lines, single targeting of EGFR with erlotinib or PI3K with BKM120 suppressed cellular growth without inducing significant apoptosis. Cotargeting of EGFR and PI3K synergistically inhibited SCCHN cell line and xenograft tumor growth, but induced variable apoptosis; some lines were highly sensitive, others were resistant. Mechanistic studies revealed that the combination inhibited both axes of the mTORC1 (S6 and 4EBP1) pathway in apoptosissensitive cell lines along with translational inhibition of Bcl-2, Bcl-xL, and Mcl-1, but failed to inhibit p-4EBP1, Bcl-2, Bcl-xL, and Mcl-1 in an apoptosis-resistant cell line. siRNA-mediated knockdown of eIF4E inhibited Bcl-2 and Mcl-1 and sensitized this cell line to apoptosis. Our results strongly suggest that cotargeting of EGFR and PI3K is synergistic and induces apoptosis of SCCHN cell lines by inhibiting both axes of the AKT-mTOR pathway and translational regulation of antiapoptotic Bcl-2 proteins. These findings may guide the development of clinical trials using this combination of agents. (C)2017 AACR.