2. Academic Validation
  3. A ribosomal gene panel predicting a novel synthetic lethality in non-BRCAness tumors

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

  • Signal Transduct Target Ther. 2023 May 10;8(1):183. doi: 10.1038/s41392-023-01401-y.
Chao Zhang # 1 2,  Qiang Guo # 3,  Lifeng Chen # 4 5,  Zheming Wu 2,  Xiao-Jian Yan 6,  Chengyang Zou 6,  Qiuxue Zhang 7,  Jiahong Tan 8,  Tian Fang 8,  Qunxian Rao 9,  Yang Li 10,  Shizhen Shen 11,  Min Deng 2,  Liewei Wang 12,  Huanyao Gao 12,  Jia Yu 12,  Hu Li 12,  Cheng Zhang 12,  Somaira Nowsheen 13,  Jake Kloeber 2,  Fei Zhao 2,  Ping Yin 2,  Chunbo Teng 14,  Zhongqiu Lin 9,  Kun Song 15,  Shuzhong Yao 16,  Liangqing Yao 17,  Lingying Wu 18,  Yong Zhang 19,  Xiaodong Cheng 20 21,  Qinglei Gao 22,  Jian Yuan 23 24,  Zhenkun Lou 25,  Jin-San Zhang 26 27
Affiliations

Affiliations

  • 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 Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Reproductive Health Research, 310006, Hangzhou, Zhejiang, China. chengxd@zju.edu.cn.
  • 21 Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, 310006, Hangzhou, Zhejiang, China. chengxd@zju.edu.cn.
  • 22 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. qingleigao@hotmail.com.
  • 23 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. yuanjian229@hotmail.com.
  • 24 Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, 200120, Shanghai, China. yuanjian229@hotmail.com.
  • 25 Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. Lou.zhenkun@mayo.edu.
  • 26 The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, 324000, Quzhou, Zhejiang, China. Zhang_jinsan@WMU.edu.cn.
  • 27 Medical Research Center, and Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, Zhejiang, China. Zhang_jinsan@WMU.edu.cn.
  • # Contributed equally.
PMID: 37160887 DOI: 10.1038/s41392-023-01401-y
Abstract

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.

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