Proteogenomics of clear cell renal cell carcinoma response to tyrosine kinase inhibitor

Hailiang Zhang, Lin Bai, Xin-Qiang Wu, Xi Tian, Jinwen Feng, Xiaohui Wu, Guo-Hai Shi, Xiaoru Pei, Jiacheng Lyu, Guojian Yang, Yang Liu, Wenhao Xu, Aihetaimujiang Anwaier, Yu Zhu, Da-Long Cao, Fujiang Xu, Yue Wang, Hua-Lei Gan, Meng-Hong Sun, Jian-Yuan Zhao (), Yuanyuan Qu (), Dingwei Ye () and Chen Ding ()
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Hailiang Zhang: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Lin Bai: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Xin-Qiang Wu: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Xi Tian: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Jinwen Feng: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Xiaohui Wu: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Guo-Hai Shi: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Xiaoru Pei: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Jiacheng Lyu: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Guojian Yang: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Yang Liu: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Wenhao Xu: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Aihetaimujiang Anwaier: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Yu Zhu: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Da-Long Cao: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Fujiang Xu: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Yue Wang: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Hua-Lei Gan: Shanghai Medical College, Shanghai Genitourinary Cancer Institute
Meng-Hong Sun: Shanghai Medical College, Shanghai Genitourinary Cancer Institute
Jian-Yuan Zhao: Shanghai Jiao Tong University School of Medicine
Yuanyuan Qu: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Dingwei Ye: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University
Chen Ding: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract The tyrosine kinase inhibitor (TKI) Sunitinib is one the therapies approved for advanced renal cell carcinoma. Here, we undertake proteogenomic profiling of 115 tumors from patients with clear cell renal cell carcinoma (ccRCC) undergoing Sunitinib treatment and reveal the molecular basis of differential clinical outcomes with TKI therapy. We find that chromosome 7q gain-induced mTOR signaling activation is associated with poor therapeutic outcomes with Sunitinib treatment, whereas the aristolochic acid signature and VHL mutation synergistically caused enhanced glycolysis is correlated with better prognosis. The proteomic and phosphoproteomic analysis further highlights the responsibility of mTOR signaling for non-response to Sunitinib. Immune landscape characterization reveals diverse tumor microenvironment subsets in ccRCC. Finally, we construct a multi-omics classifier that can detect responder and non-responder patients (receiver operating characteristic–area under the curve, 0.98). Our study highlights associations between ccRCC molecular characteristics and the response to TKI, which can facilitate future improvement of therapeutic responses.

Date: 2023
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DOI: 10.1038/s41467-023-39981-6

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