Co-targeting EGFR and mTOR with gefitinib and everolimus in triple-negative breast cancer cells
Co-targeting EGFR and mTOR with gefitinib and everolimus in triple-negative breast cancer cells
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DOI：
10.1038/s41598-020-63310-2
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发表时间：
2020-04-14
影响因子：
4.6
通讯作者：
Aubel, Corinne
中科院分区：
文献类型：
--
作者：
El Guerrab, Abderrahim;Bamdad, Mahchid;Aubel, Corinne
三阴性乳腺癌（TNBC）不太可能对激素疗法和抗HER 2靶向疗法有反应。TNBC过表达EGFR并表现出PI 3 K/AKT/mTOR信号传导途径的组成性激活。我们假设同时阻断EGFR和mTOR可能是治疗TNBC的潜在治疗策略。我们检测了mTOR抑制剂依维莫司联合EGFR酪氨酸激酶抑制剂吉非替尼在有或没有PI 3 K/AKT/mTOR信号通路激活突变的TNBC细胞中的抗肿瘤活性。我们证明依维莫司和吉非替尼在PI 3 K和PTEN突变的CAL-51细胞系中诱导协同生长抑制，但在PTEN缺失的HCC-1937细胞系中不诱导。抗增殖作用与mTOR和P70 S6 K磷酸化的协同抑制以及CAL-51细胞系中4 E-BP 1活化的显著降低相关。我们还发现，联合治疗显着抑制细胞周期的进展，并增加在这个细胞系的凋亡。基因和蛋白质表达分析显示，暴露于联合治疗后，细胞周期调节剂的显着下调。总的来说，这些结果表明mTOR和EGFR的双重抑制可能是具有PI 3 K激活突变的TNBC的有效治疗。
Triple-negative breast cancers (TNBC) are unlikely to respond to hormonal therapies and anti-HER2-targeted therapies. TNBCs overexpress EGFR and exhibit constitutive activation of the PI3K/AKT/mTOR signalling pathway. We hypothesized that simultaneously blocking EGFR and mTOR could be a potential therapeutic strategy for the treatment of TNBC. We examined the antitumour activity of the mTOR inhibitor everolimus combined with the EGFR tyrosine kinase inhibitor gefitinib in TNBC cell with or without activating mutations in the PI3K/AKT/mTOR signalling pathway. We demonstrated that everolimus and gefitinib induced synergistic growth inhibition in the PI3K and PTEN-mutant CAL-51 cell line but not in the PTEN-null HCC-1937 cell line. The antiproliferative effect was associated with synergistic inhibition of mTOR and P70S6K phosphorylation, as well as a significant reduction in 4E-BP1 activation in the CAL-51 cell line. We also showed that combination therapy significantly inhibited cell cycle progression and increased apoptosis in this cell line. Gene and protein expression analysis revealed significant downregulation of cell cycle regulators after exposure to combined treatment. Collectively, these results suggested that dual inhibition of mTOR and EGFR may be an effective treatment for TNBC with activating mutations of PI3K.