Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion

• Published in: Cancer cell Vol. 38; no. 1; pp. 79 - 96.e11
• Main Authors: Su, Rui, Dong, Lei, Li, Yangchan, Gao, Min, Han, Li, Wunderlich, Mark, Deng, Xiaolan, Li, Hongzhi, Huang, Yue, Gao, Lei, Li, Chenying, Zhao, Zhicong, Robinson, Sean, Tan, Brandon, Qing, Ying, Qin, Xi, Prince, Emily, Xie, Jun, Qin, Hanjun, Li, Wei, Shen, Chao, Sun, Jie, Kulkarni, Prakash, Weng, Hengyou, Huang, Huilin, Chen, Zhenhua, Zhang, Bin, Wu, Xiwei, Olsen, Mark J., Müschen, Markus, Marcucci, Guido, Salgia, Ravi, Li, Ling, Fathi, Amir T., Li, Zejuan, Mulloy, James C., Wei, Minjie, Horne, David, Chen, Jianjun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.07.2020
• Subjects: Alpha-Ketoglutarate-Dependent Dioxygenase FTO - antagonists & inhibitors; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - chemistry; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - metabolism; Anthracenes - chemistry; Anthracenes - pharmacology; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Cell Line, Tumor; Cell Self Renewal - drug effects; Cell Survival - drug effects; Cell Survival - genetics; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; FTO; Gene Expression Regulation, Neoplastic - drug effects; Humans; immune checkpoint genes; immune evasion; Immune Evasion - drug effects; Immune Evasion - genetics; inhibitors; leukemia; Leukemia - genetics; Leukemia - pathology; Leukemia - prevention & control; LILRB4; LSC/LIC self-renewal; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Molecular Structure; N6-methyladenosine (m6A) modification; Protein Binding - drug effects; Protein Domains; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; solid tumors; therapeutics; U937 Cells; FTO; inhibitors; leukemia; therapeutics; immune evasion; N6-methyladenosine (m6A) modification; LSC/LIC self-renewal; immune checkpoint genes; LILRB4; solid tumors; N-methyladenosine (mA) modification
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2020.04.017

Fat mass and obesity-associated protein (FTO), an RNA N6-methyladenosine (m6A) 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. [Display omitted] •Development of two potent FTO inhibitors with IC50 values in the low nanomolar range•KD of FTO or pharmacological inhibition of FTO suppresses LSC/LIC self-renewal•Targeting FTO suppresses immune checkpoint gene expression and immune evasion•Targeting FTO by potent inhibitors holds therapeutic promise against various cancers Su et al. develop two potent small-molecule inhibitors against an RNA N6-methyladenosine demethylase called FTO. FTO inhibition shows anti-tumor effects in several types of cancers in mouse models by restricting self-renewal of cancer stem cells and suppressing immune evasion.