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WEE1 inhibitor, AZD1775, overcomes trastuzumab resistance by targeting cancer stem-like properties in HER2-positive breast cancer.
Cancer Letters ( IF 9.7 ) Pub Date : 2019-12-19 , DOI: 10.1016/j.canlet.2019.12.023
Andrea Sand 1 , Mitchel Piacsek 1 , Deborah L Donohoe 1 , Aspen T Duffin 1 , Geoffrey T Riddell 1 , Chaoyang Sun 2 , Ming Tang 3 , Richard A Rovin 4 , Judy A Tjoe 5 , Jun Yin 1
Affiliation  

Although trastuzumab has greatly improved the outcome of HER2-positive breast cancer, the emergence of resistance hampers its clinical benefits. Trastuzumab resistance is a multi-factorial consequence predominantly due to presence of cancer stem-like cells (CSCs). AZD1775, a potent anti-cancer agent targeting WEE1 kinase to drive tumor cells with DNA damage to premature mitosis, has previously shown high efficacies when targeting different cancers with a well-tolerated cytotoxic profile, but has not been evaluated in trastuzumab-resistant (TrR) breast cancer. We sought to investigate the effect of AZD1775 on cancer stem-like cell (CSC) properties, apoptosis, cell cycle regulation in TrR breast cancer. Our study for the first time demonstrated that AZD1775 induces apoptosis and arrests TrR cells at G2/M phase. More importantly, AZD1775 effectively targeted CSC properties by suppressing MUC1 expression levels. AZD1775 administration also induced apoptosis in our in-house patient-derived tumor cell line at passage 0, implying its significant clinical relevance. These findings highlight the potential clinical application of AZD1775 in overcoming trastuzumab resistance in breast cancer.

中文翻译:

WEE1抑制剂AZD1775通过靶向HER2阳性乳腺癌的癌变样特性来克服曲妥珠单抗的耐药性。

尽管曲妥珠单抗已大大改善了HER2阳性乳腺癌的预后,但耐药性的出现妨碍了其临床益处。曲妥珠单抗的耐药性是多因素后果,主要是由于存在癌干样细胞(CSC)。AZD1775是一种针对WEE1激酶的有效抗癌剂,可驱动具有DNA损伤的肿瘤细胞导致早幼有丝分裂,此前针对具有良好耐受性的细胞毒性谱的不同癌症具有很高的疗效,但尚未评估其对曲妥珠单抗的耐药性(TrR ) 乳腺癌。我们试图研究AZD1775对TrR乳腺癌中癌干样细胞(CSC)特性,细胞凋亡,细胞周期调控的影响。我们的研究首次证明AZD1775诱导细胞凋亡并使TrR细胞停滞在G2 / M期。更重要的是,AZD1775通过抑制MUC1表达水平有效靶向CSC特性。AZD1775给药还在第0代时诱导了我们内部患者来源的肿瘤细胞系的凋亡,这表明它具有重要的临床意义。这些发现突出了AZD1775在克服曲妥珠单抗对乳腺癌的耐药性方面的潜在临床应用。
更新日期:2019-12-19
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