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The novel BET degrader, QCA570, is highly active against the growth of human NSCLC cells and synergizes with osimertinib in suppressing osimertinib-resistant EGFR-mutant NSCLC cells.

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机构： [1]Department of Oncology, The Second Xiangya Hospital, Central South University Changsha 410011, Hunan, China. [2]Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute Atlanta, GA 30322, USA. [3]Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University Nanjing 210009, Jiangsu, China. [4]Department of Thoracic Surgery, West China Hospital, Sichuan University Chengdu 610041, Sichuan, China. [5]Department of Biostatistics and Bioinformatics, Rollins School of Public Health of Emory University Atlanta, GA 30322, USA. [6]Department of Medicinal Chemistry, University of Michigan Ann Arbor, MI 48109, USA.

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Lung cancer remains the leading cause of cancer deaths worldwide despite advances in knowledge in cancer biology and options of various targeted therapies. Efforts in identifying innovative and effective therapies are still highly appreciated. Targeting bromodomain and extra terminal (BET) proteins that function as epigenetic readers and master transcription coactivators is now a potential cancer therapeutic strategy. The current study evaluates the therapeutic efficacies of the novel BET degrader, QCA570, in lung cancer and explores its underlying mechanisms. QCA570 at low nanomolar ranges effectively decreased the survival of a panel of human lung cancer cell lines with induction of apoptosis in vitro. As expected, it potently induced degradation of BET proteins including BRD4, BRD3 and BRD2. Moreover, it potently decreased Mcl-1 levels due to transcriptional suppression and protein degradation; this event is critical for mediating apoptosis induced by QCA570. Moreover, QCA570 synergized with osimertinib in suppressing the growth of osimertinib-resistant cells in vitro and in vivo, suggesting potential in overcoming acquired resistance to osimertinib. These preclinical findings support the potential of QCA570 in treatment of lung cancer either as a single agent or in combination with others.AJCR Copyright © 2022.

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出版当年[2022]版：

大类 | 3 区医学

小类 | 3 区肿瘤学

最新[2023]版：

大类 | 3 区医学

小类 | 3 区肿瘤学

第一作者：

第一作者机构： [1]Department of Oncology, The Second Xiangya Hospital, Central South University Changsha 410011, Hunan, China. [2]Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute Atlanta, GA 30322, USA.

通讯作者：

通讯机构： [2]Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute Atlanta, GA 30322, USA. [*1]Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, 1365-C Clifton Road, C3088, Atlanta, GA 30322, USA.

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