抑制 PI3K/Akt/mTOR 可克服三阴性乳腺癌细胞系 HCC38 对顺铂的耐药性。
Inhibition of PI3K/Akt/mTOR overcomes cisplatin resistance in the triple negative breast cancer cell line HCC38.
机构信息
Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany.
出版信息
BMC Cancer. 2017 Nov 3;17(1):711. doi: 10.1186/s12885-017-3695-5.
BACKGROUND
Widely established targeted therapies directed at triple negative breast cancer (TNBC) are missing. Classical chemotherapy remains the systemic treatment option. Cisplatin has been tested in TNBC but bears the disadvantage of resistance development. The purpose of this study was to identify resistance mechanisms in cisplatin-resistant TNBC cell lines and select targeted therapies based on these findings.
METHODS
The TNBC cell lines HCC38 and MDA-MB231 were subjected to intermittent cisplatin treatment resulting in the 3.5-fold cisplatin-resistant subclone HCC38CisR and the 2.1-fold more resistant MDA-MB231CisR. Activation of pro-survival pathways was explored by immunostaining of phospho-receptor tyrosine kinases. Targeted therapies (NVP-AEW541, lapatinib and NVP-BEZ235) against activated pathways were investigated regarding cancer cell growth and cisplatin sensitivity.
RESULTS
In HCC38CisR and MDA-MB231CisR, phosphorylation of epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R) was observed. In HCC38CisR, treatment with NVP-AEW541 increased potency of lapatinib almost seven-fold, but both compounds could not restore cisplatin sensitivity. However, the dual phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 acted synergistically with cisplatin in HCC38CisR and fully restored cisplatin sensitivity. Similarly, NVP-BEZ235 increased cisplatin potency in MDA-MB231CisR. Furthermore, NVP-AEW541 in combination with lapatinib restored cisplatin sensitivity in MDA-MB231CisR.
CONCLUSION
Simultaneous inhibition of EGFR and IGF1R in cisplatin-resistant TNBC cell lines was synergistic regarding inhibition of proliferation and induction of apoptosis. Co-treatment with NVP-BEZ235 or with a combination of NVP-AEW541 and lapatinib restored cisplatin sensitivity and may constitute a targeted treatment option for cisplatin-resistant TNBC.
背景
针对三阴性乳腺癌（TNBC）的广泛应用的靶向治疗方法仍然缺失。经典的化疗仍然是系统治疗的选择。顺铂已在 TNBC 中进行了测试，但存在耐药性发展的缺点。本研究的目的是确定顺铂耐药性 TNBC 细胞系中的耐药机制，并根据这些发现选择靶向治疗方法。
方法
TNBC 细胞系 HCC38 和 MDA-MB231 接受间歇性顺铂治疗，导致 3.5 倍顺铂耐药亚克隆 HCC38CisR 和 2.1 倍更耐药 MDA-MB231CisR。通过磷酸化受体酪氨酸激酶的免疫染色来探索促生存途径的激活。针对激活途径的靶向治疗（NVP-AEW541、拉帕替尼和 NVP-BEZ235）被用于研究对癌细胞生长和顺铂敏感性的影响。
结果
在 HCC38CisR 和 MDA-MB231CisR 中，观察到表皮生长因子受体（EGFR）和胰岛素样生长因子 1 受体（IGF1R）的磷酸化。在 HCC38CisR 中，NVP-AEW541 的治疗使拉帕替尼的效力增加了近 7 倍，但这两种化合物都不能恢复顺铂的敏感性。然而，双重磷脂酰肌醇 3-激酶（PI3K）和哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂 NVP-BEZ235 在 HCC38CisR 中与顺铂协同作用，完全恢复了顺铂的敏感性。同样，NVP-BEZ235 增加了 MDA-MB231CisR 中顺铂的效力。此外，NVP-AEW541 联合拉帕替尼恢复了 MDA-MB231CisR 中顺铂的敏感性。
结论
在顺铂耐药性 TNBC 细胞系中同时抑制 EGFR 和 IGF1R 对抑制增殖和诱导凋亡具有协同作用。NVP-BEZ235 或 NVP-AEW541 联合拉帕替尼的联合治疗恢复了顺铂的敏感性，可能成为顺铂耐药性 TNBC 的靶向治疗选择。
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