联合靶向表皮生长因子受体（EGFR）和Src作为治疗三阴性乳腺癌的一种潜在新疗法。
Combined targeting EGFR and SRC as a potential novel therapeutic approach for the treatment of triple negative breast cancer.
作者信息
Canonici Alexandra, Browne Alacoque L, Ibrahim Mohamed F K, Fanning Kevin P, Roche Sandra, Conlon Neil T, O'Neill Fiona, Meiller Justine, Cremona Mattia, Morgan Clare, Hennessy Bryan T, Eustace Alex J, Solca Flavio, O'Donovan Norma, Crown John
机构信息
National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
Medical Oncology Group, Department of Molecular Medicine, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland.
出版信息
Ther Adv Med Oncol. 2020 Jan 28;12:1758835919897546. doi: 10.1177/1758835919897546. eCollection 2020.
BACKGROUND
Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. Epidermal growth factor receptor (EGFR) has been shown to be over-expressed in TNBC and represents a rational treatment target.
METHODS
We examined single agent and combination effects for afatinib and dasatinib in TNBC. We then determined IC and combination index values using Calcusyn. Functional analysis of single and combination treatments was performed using reverse phase protein array and cell cycle analysis. Finally, we determined the anticancer effects of the combination .
RESULTS
A total of 14 TNBC cell lines responded to afatinib with IC values ranging from 0.008 to 5.0 µM. Three cell lines, belonging to the basal-like subtype of TNBC, were sensitive to afatinib. The addition of afatinib enhanced response to the five other targeted therapies in HCC1937 and HDQP1 cells. The combination of afatinib with dasatinib caused the greatest growth inhibition in both cell lines. The afatinib/dasatinib combination was synergistic and/or additive in 13/14 TNBC cell lines. Combined afatinib/dasatinib treatment induced G1 cell cycle arrest. Reverse phase protein array results showed the afatinib/dasatinib combination resulted in efficient inhibition of both pERK(T202/T204) and pAkt(S473) signalling in BT20 cells, which was associated with the greatest antiproliferative effects. High baseline levels of pSrc(Y416) and pMAPK(p38) correlated with sensitivity to afatinib, whereas low levels of B-cell lymphoma 2 (Bcl2) and mammalian target of rapamycin (mTOR) correlated with synergistic growth inhibition by combined afatinib and dasatinib treatment. , the combination treatment inhibited tumour growth in a HCC1806 xenograft model.
CONCLUSIONS
We demonstrate that afatinib combined with dasatinib has potential clinical activity in TNBC but warrants further preclinical investigation.
背景
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，治疗选择有限。表皮生长因子受体（EGFR）已被证明在TNBC中过度表达，是一个合理的治疗靶点。
方法
我们研究了阿法替尼和达沙替尼在TNBC中的单药及联合作用。然后使用Calcusyn确定IC和联合指数值。使用反相蛋白质阵列和细胞周期分析对单药及联合治疗进行功能分析。最后，我们确定了联合治疗的抗癌效果。
结果
总共14种TNBC细胞系对阿法替尼有反应，IC值范围为0.008至5.0μM。三种属于TNBC基底样亚型的细胞系对阿法替尼敏感。在HCC1937和HDQP1细胞中，添加阿法替尼增强了对其他五种靶向治疗的反应。阿法替尼与达沙替尼联合在两种细胞系中均引起最大程度的生长抑制。阿法替尼/达沙替尼联合在13/14种TNBC细胞系中具有协同和/或相加作用。阿法替尼/达沙替尼联合治疗诱导G1期细胞周期停滞。反相蛋白质阵列结果显示，阿法替尼/达沙替尼联合在BT20细胞中有效抑制了pERK（T202/T204）和pAkt（S473）信号传导，这与最大的抗增殖作用相关。pSrc（Y416）和pMAPK（p38）的高基线水平与对阿法替尼的敏感性相关，而低水平的B细胞淋巴瘤2（Bcl2）和雷帕霉素靶蛋白（mTOR）与阿法替尼和达沙替尼联合治疗的协同生长抑制相关。此外，联合治疗在HCC1806异种移植模型中抑制了肿瘤生长。
结论
我们证明阿法替尼联合达沙替尼在TNBC中具有潜在的临床活性，但需要进一步的临床前研究。
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