Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion.

Rui Su, Lei Dong, Yangchan Li, Min Gao, Li Han, Mark Wunderlich, Xiaolan Deng, Hongzhi Li, Yue Huang, Lei Gao, Chenying Li, Zhicong Zhao, Sean Robinson, Brandon Tan, Ying Qing, Xi Qin, Emily Prince, Jun Xie, Hanjun Qin, Wei Li, Chao Shen, Jie Sun, Prakash Kulkarni, Hengyou Weng, Huilin Huang, Zhenhua Chen, Bin Zhang, Xiwei Wu, Mark J Olsen, Markus Müschen, Guido Marcucci, Ravi Salgia, Ling Li, Amir T Fathi, Zejuan Li, James C Mulloy, Minjie Wei, David Horne, Jianjun Chen

Journal: Cancer cell 2021;38(1):79-96.e11

PMID: 32531268

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Abstract

Fat mass and obesity-associated protein (FTO), an RNA N-methyladenosine (mA) demethylase, plays oncogenic roles in various cancers, presenting an opportunity for the development of effective targeted therapeutics. Here, we report two potent small-molecule FTO inhibitors that exhibit strong anti-tumor effects in multiple types of cancers. We show that genetic depletion and pharmacological inhibition of FTO dramatically attenuate leukemia stem/initiating cell self-renewal and reprogram immune response by suppressing expression of immune checkpoint genes, especially LILRB4. FTO inhibition sensitizes leukemia cells to T cell cytotoxicity and overcomes hypomethylating agent-induced immune evasion. Our study demonstrates that FTO plays critical roles in cancer stem cell self-renewal and immune evasion and highlights the broad potential of targeting FTO for cancer therapy.

Address: Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineer (Tianjin), Tianjin University, Tianjin 300072, China.; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Pathology and Genomic Medicine, Houston Methodist, Houston, TX 77030, USA.; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Hematology, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang 31003, China.; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.; The Integrative Genomics Core, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA.; Department of Hematologic Malignancies Translational Science, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.; Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA 91010, USA.; Department of Hematologic Malignancies Translational Science, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA.; Department of Pharmaceutical Sciences, College of Pharmacy-Glendale, Midwestern University, Glendale, AZ 85308, USA.; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA.; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.; Department of Pathology and Genomic Medicine, Houston Methodist, Houston, TX 77030, USA.; School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA. Electronic address: [email protected].

DOI: 10.1016/j.ccell.2020.04.017