Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion

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-tu...

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Bibliographic Details
Published in:Cancer cell 2020-07, Vol.38 (1), p.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: Article
Language:English
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
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Summary: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.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccell.2020.04.017