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Cotargeting CHK1 and PI3K Synergistically Suppresses Tumor Growth of Oral Cavity Squamous Cell Carcinoma in Patient-Derived Xenografts

1
Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
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Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
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Department of Otolaryngology Head and Neck Surgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
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Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan
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Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
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Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
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College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
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Department of Pathology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
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Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
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Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
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Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(7), 1726; https://doi.org/10.3390/cancers12071726
Received: 26 May 2020 / Revised: 23 June 2020 / Accepted: 26 June 2020 / Published: 29 June 2020
(This article belongs to the Section Cancer Therapy)
Oral cavity squamous cell carcinomas (OSCCs) are aggressive tumors, and their recurrence leads to poor prognosis and reduced survival rates. This study aimed to identify therapeutic targets and to evaluate the efficacy of targeted inhibitors in OSCC patient-derived xenograft (PDX) models. Herein, we reported that OSCC PDXs recapitulated the genomic signatures of their paired primary tumors and the expression of CHEK1, PIK3CA, and PIK3CD was significantly upregulated in OSCC. The antitumor efficacy of CHK1 inhibitors (PF477736, AZD7762, LY2606368) and PI3K inhibitors (BYL719, GDC0941, GSK1059615) was investigated in OSCC cell lines and PDX models. Targeting either CHK1 or PI3K effectively inhibited cell proliferation and colony formation by inducing cell cycle arrest and apoptosis in in vitro cell-based assays. Cisplatin-based chemotherapy combined with CHK1 inhibitor treatment synergistically inhibited cell proliferation by suppressing CHK1 phosphorylation and inducing PARP cleavage. Furthermore, compared with monotherapy, cotreatment with CHK1 and PI3K inhibitors exerted synergistic anticancer effects by suppressing CHK1, AKT, and 4E-BP1 phosphorylation. In summary, our study identified CHK1 and PI3K as promising targets, especially in a dual treatment strategy combining a CHK1 inhibitor with cisplatin or a PI3K inhibitor as a novel therapeutic approach for OSCC patients with aberrant cell cycle regulation and PI3K signaling activation. View Full-Text
Keywords: oral cavity squamous cell carcinomas; CHK1; PI3K; patient-derived xenograft oral cavity squamous cell carcinomas; CHK1; PI3K; patient-derived xenograft
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Yang, C.-Y.; Liu, C.-R.; Chang, I. .-F.; OuYang, C.-N.; Hsieh, C.-H.; Huang, Y.-L.; Wang, C.-I.; Jan, F.-W.; Wang, W.-L.; Tsai, T.-L.; Liu, H.; Tseng, C.-P.; Chang, Y.-S.; Wu, C.-C.; Chang, K.-P. Cotargeting CHK1 and PI3K Synergistically Suppresses Tumor Growth of Oral Cavity Squamous Cell Carcinoma in Patient-Derived Xenografts. Cancers 2020, 12, 1726.

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