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A ribosomal gene panel predicting a novel synthetic lethality in non-BRCAness tumors

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收录情况: ◇ SCIE ◇ 统计源期刊 ◇ CSCD-C ◇ 卓越:领军期刊

单位: [1]Beijing Institute of Basic Medical Sciences, 100850 Beijing, China [2]Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA [3]School of Pharmaceutical Sciences, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China [4]Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People’s Hospital, 310014 Hangzhou, Zhejiang, China [5]Department of Gynecology, Zhejiang Provincial People’s Hospital, 310014 Hangzhou, Zhejiang, China [6]Department of Gynecology, the First Affiliated Hospital of Wenzhou Medical University, 325000 Wenzhou, Zhejiang, China [7]Wuhan Kingwise Biotechnology Co., Ltd., 430206 Wuhan, Hubei, China [8]Cancer Biology Research Center (Key Laboratory of the Ministry of Education),Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,430030 Wuhan,Hubei,China [9]Department of Gynecological Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, Guangdong, China [10]Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Reproductive Health Research, 310006 Hangzhou, Zhejiang, China [11]Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, 310006 Hangzhou, Zhejiang, China [12]Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA [13]Department of Dermatology, University of California San Diego, San Diego, CA 92122, USA [14]Key Laboratory of Saline-alkali Vegetation Ecology Restoration, Ministry of Education, College of Life Science, Northeast Forestry University, 150040 Harbin, China [15]Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 250012 Jinan, Shandong, China [16]Department of Obstetrics and Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, 510080 Guangzhou, Guangdong, China [17]Department of Gynecologic Oncology, Obstetrics and Gynecology Hospital of Fudan University, 200090 Shanghai, China [18]Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021 Beijing, China [19]Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China [20]Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, 310006 Hangzhou, Zhejiang, China [21]Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, 200120 Shanghai, China [22]Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, 200120 Shanghai, China [23]The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, 324000 Quzhou, Zhejiang, China [24]Medical Research Center, and Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, 325000 Wenzhou, Zhejiang, China
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Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination (HR) deficiency. However, many patients without apparent HR defects also respond well to PARP inhibitors/cisplatin. The biomarker responsible for this mechanism remains unclear. Here, we identified a set of ribosomal genes that predict response to PARP inhibitors/cisplatin in HR-proficient patients. PARP inhibitor/cisplatin selectively eliminates cells with high expression of the eight genes in the identified panel via DNA damage (ATM) signaling-induced pro-apoptotic ribosomal stress, which along with ATM signaling-induced pro-survival HR repair constitutes a new model to balance the cell fate in response to DNA damage. Therefore, the combined examination of the gene panel along with HR status would allow for more precise predictions of clinical response to PARP inhibitor/cisplatin. The gene panel as an independent biomarker was validated by multiple published clinical datasets, as well as by an ovarian cancer organoids library we established. More importantly, its predictive value was further verified in a cohort of PARP inhibitor-treated ovarian cancer patients with both RNA-seq and WGS data. Furthermore, we identified several marketed drugs capable of upregulating the expression of the genes in the panel without causing HR deficiency in PARP inhibitor/cisplatin-resistant cell lines. These drugs enhance PARP inhibitor/cisplatin sensitivity in both intrinsically resistant organoids and cell lines with acquired resistance. Together, our study identifies a marker gene panel for HR-proficient patients and reveals a broader application of PARP inhibitor/cisplatin in cancer therapy.© 2023. The Author(s).

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出版当年[2022]版:
大类 | 1 区 医学
小类 | 1 区 生化与分子生物学 1 区 细胞生物学
最新[2025]版:
大类 | 1 区 医学
小类 | 1 区 生化与分子生物学 1 区 细胞生物学
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出版当年[2021]版:
Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 CELL BIOLOGY
最新[2023]版:
Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 CELL BIOLOGY

影响因子: 最新[2023版] 最新五年平均 出版当年[2021版] 出版当年五年平均 出版前一年[2020版] 出版后一年[2022版]

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第一作者单位: [1]Beijing Institute of Basic Medical Sciences, 100850 Beijing, China [2]Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
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通讯机构: [10]Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Reproductive Health Research, 310006 Hangzhou, Zhejiang, China [20]Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, 310006 Hangzhou, Zhejiang, China [21]Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, 200120 Shanghai, China [22]Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, 200120 Shanghai, China [23]The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, 324000 Quzhou, Zhejiang, China [24]Medical Research Center, and Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, 325000 Wenzhou, Zhejiang, China
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