Stratification of patients with clear cell renal cell carcinoma to facilitate drug repositioning
Xiangyu Li,
Woonghee Kim,
Kajetan Juszczak,
Muhammad Arif,
Yusuke Sato,
Haruki Kume,
Seishi Ogawa,
Hasan Turkez,
Jan Boren,
Jens Nielsen,
Mathias Uhlen,
Cheng Zhang,
Adil Mardinoglu
Affiliations
Xiangyu Li
Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden; Bash Biotech Inc, 600 West Broadway, Suite 700, San Diego, CA 92101, USA
Woonghee Kim
Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden
Kajetan Juszczak
Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden
Muhammad Arif
Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden
Yusuke Sato
Department of Pathology and Tumor Biology, Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan; Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
Haruki Kume
Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
Seishi Ogawa
Department of Pathology and Tumor Biology, Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan; Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm 17177, Sweden
Hasan Turkez
Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey
Jan Boren
Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg 41345, Sweden
Jens Nielsen
Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg 41296, Sweden; BioInnovation Institute, Copenhagen N 2200, Denmark
Mathias Uhlen
Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden
Cheng Zhang
Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden; Key Laboratory of Advanced Drug Preparation Technologies, School of Pharmaceutical Sciences, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China; Corresponding author
Adil Mardinoglu
Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK; Corresponding author
Summary: Clear cell renal cell carcinoma (ccRCC) is the most common histological type of kidney cancer and has high heterogeneity. Stratification of ccRCC is important since distinct subtypes differ in prognosis and treatment. Here, we applied a systems biology approach to stratify ccRCC into three molecular subtypes with different mRNA expression patterns and prognosis of patients. Further, we developed a set of biomarkers that could robustly classify the patients into each of the three subtypes and predict the prognosis of patients. Then, we reconstructed subtype-specific metabolic models and performed essential gene analysis to identify the potential drug targets. We identified four drug targets, including SOAT1, CRLS1, and ACACB, essential in all the three subtypes and GPD2, exclusively essential to subtype 1. Finally, we repositioned mitotane, an FDA-approved SOAT1 inhibitor, to treat ccRCC and showed that it decreased tumor cell viability and inhibited tumor cell growth based on in vitro experiments.
