NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest.
NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest.
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DOI：
10.1038/s41389-018-0051-9
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发表时间：
2018-05-25
期刊：
影响因子：
6.2
通讯作者：
Checquolo S
中科院分区：
文献类型：
--
作者：
Diluvio G;Del Gaudio F;Giuli MV;Franciosa G;Giuliani E;Palermo R;Besharat ZM;Pignataro MG;Vacca A;d'Amati G;Maroder M;Talora C;Capalbo C;Bellavia D;Checquolo S
Notch失调与许多肿瘤有关，包括三阴性乳腺癌（TNBC），这是临床结果最差的乳腺癌亚型。然而，单个受体在TNBC中的重要性及其特定的作用机制仍有待阐明，即使最近的研究结果表明活化的Notch 3在TNBC亚组中的特定作用。表皮生长因子受体（EGFR）在TNBC中过表达，但抗EGFR药物（包括酪氨酸激酶抑制剂，TKI）尚未被批准用于治疗这些患者，因为临床试验显示出令人失望的结果。对EGFR阻滞剂的耐药性是常见的。在这里，我们表明Notch 3特异性抑制增加了TNBC抗性细胞中TNBC对TKI-吉非替尼的敏感性。从机制上讲，我们证明了Notch 3能够调节活化的EGFR膜定位到脂筏微结构域中，因为Notch 3抑制，例如筏耗尽，诱导EGFR内化及其细胞内阻滞，而不涉及受体降解。有趣的是，这些事件与蛋白酪氨酸磷酸酶H1（PTPH 1）在Y1173残基（但不在Y1068）处的EGFR酪氨酸去磷酸化相关，因此表明其可能参与观察到的Notch 3依赖性TNBC对吉非替尼的敏感性反应。与该观点一致，在EGFR和Notch 3的组合阻断后观察到磷酸-EGFR的核定位缺陷，这导致TNBC细胞存活降低。值得注意的是，我们通过计算机基因表达和人TNBC原代样品的免疫组织化学分析观察到EGFR和N 0 TCH 3表达水平之间的显著相关性。我们的研究结果强烈表明，TKI-吉非替尼与Notch 3特异性抑制的联合疗法可作为TNBC治疗中的药物组合优势。
Notch dysregulation has been implicated in numerous tumors, including triple-negative breast cancer (TNBC), which is the breast cancer subtype with the worst clinical outcome. However, the importance of individual receptors in TNBC and their specific mechanism of action remain to be elucidated, even if recent findings suggested a specific role of activated-Notch3 in a subset of TNBCs. Epidermal growth factor receptor (EGFR) is overexpressed in TNBCs but the use of anti-EGFR agents (including tyrosine kinase inhibitors, TKIs) has not been approved for the treatment of these patients, as clinical trials have shown disappointing results. Resistance to EGFR blockers is commonly reported. Here we show that Notch3-specific inhibition increases TNBC sensitivity to the TKI-gefitinib in TNBC-resistant cells. Mechanistically, we demonstrate that Notch3 is able to regulate the activated EGFR membrane localization into lipid rafts microdomains, as Notch3 inhibition, such as rafts depletion, induces the EGFR internalization and its intracellular arrest, without involving receptor degradation. Interestingly, these events are associated with the EGFR tyrosine dephosphorylation at Y1173 residue (but not at Y1068) by the protein tyrosine phosphatase H1 (PTPH1), thus suggesting its possible involvement in the observed Notch3-dependent TNBC sensitivity response to gefitinib. Consistent with this notion, a nuclear localization defect of phospho-EGFR is observed after combined blockade of EGFR and Notch3, which results in a decreased TNBC cell survival. Notably, we observed a significant correlation between EGFR and NOTCH3 expression levels by in silico gene expression and immunohistochemical analysis of human TNBC primary samples. Our findings strongly suggest that combined therapies of TKI-gefitinib with Notch3-specific suppression may be exploited as a drug combination advantage in TNBC treatment.
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影响因子：
64.5
作者：
Boelens MC;Wu TJ;Nabet BY;Xu B;Qiu Y;Yoon T;Azzam DJ;Twyman-Saint Victor C;Wiemann BZ;Ishwaran H;Ter Brugge PJ;Jonkers J;Slingerland J;Minn AJ
通讯作者：
Minn AJ
影响因子：
11.2
作者：
Hou SW;Zhi HY;Pohl N;Loesch M;Qi XM;Li RS;Basir Z;Chen G
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Chen G
影响因子：
4.2
作者：
Hirose, Hajime;Ishii, Hideshi;Mori, Masaki
通讯作者：
Mori, Masaki
影响因子：
8
作者：
Checquolo, S.;Palermo, R.;Screpanti, I.
通讯作者：
Screpanti, I.
影响因子：
4.8
作者：
Hou, Songwang;Suresh, Padmanaban S.;Chen, Guan
通讯作者：
Chen, Guan