WEE1 inhibitor, AZD1775, overcomes trastuzumab resistance by targeting cancer stem-like properties in HER2-positive breast cancer
| Autor: | Chaoyang Sun, Richard A. Rovin, Andrea Sand, Judy A. Tjoe, Deborah Donohoe, Geoffrey T. Riddell, Aspen T. Duffin, Jun Yin, Ming Tang, Mitchel Piacsek |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Receptor ErbB-2 Breast Neoplasms Cell Cycle Proteins Pyrimidinones Mice 03 medical and health sciences 0302 clinical medicine Breast cancer Trastuzumab Cancer stem cell Cell Line Tumor medicine Animals Humans Cytotoxic T cell Gene Silencing skin and connective tissue diseases Cell Proliferation WEE1 Inhibitor AZD1775 biology business.industry Cancer Protein-Tyrosine Kinases Cell cycle medicine.disease Gene Expression Regulation Neoplastic Wee1 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Neoplastic Stem Cells biology.protein Cancer research Heterografts Pyrazoles Female business medicine.drug |
| Zdroj: | Cancer Letters. 472:119-131 |
| ISSN: | 0304-3835 |
| DOI: | 10.1016/j.canlet.2019.12.023 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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