Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion

被引：597

作者：

Su, Rui ^{[1
]}

Dong, Lei ^{[1
]}

Li, Yangchan ^{[1
,11
]}

Gao, Min ^{[1
,12
,13
]}

Han, Li ^{[1
,2
]}

Wunderlich, Mark ^{[3
]}

Deng, Xiaolan ^{[1
]}

Li, Hongzhi ^{[4
]}

Huang, Yue ^{[6
]}

Gao, Lei ^{[1
,14
]}

Li, Chenying ^{[1
,15
]}

Zhao, Zhicong ^{[1
,18
]}

Robinson, Sean ^{[1
]}

Tan, Brandon ^{[1
]}

Qing, Ying ^{[1
]}

Qin, Xi ^{[1
]}

Prince, Emily ^{[1
]}

Xie, Jun

Qin, Hanjun ^{[5
]}

Li, Wei ^{[1
]}

Shen, Chao ^{[1
]}

Sun, Jie ^{[7
]}

Kulkarni, Prakash ^{[8
]}

Weng, Hengyou ^{[1
]}

Huang, Huilin ^{[1
]}

Chen, Zhenhua ^{[1
]}

Zhang, Bin ^{[7
,9
,10
]}

Wu, Xiwei ^{[5
]}

Olsen, Mark J. ^{[16
]}

Muschen, Markus ^{[1
,9
,10
]}

Marcucci, Guido ^{[7
,9
,10
]}

Salgia, Ravi ^{[8
]}

Li, Ling ^{[7
,10
]}

Fathi, Amir T. ^{[17
]}

Li, Zejuan ^{[14
]}

Mulloy, James C.

Wei, Minjie ^{[2
]}

Horne, David ^{[4
]}

Chen, Jianjun ^{[1
,9
,10
]}

机构：

[1] Beckman Res Inst City Hope, Dept Syst Biol, Monrovia, CA 91016 USA

[2] China Med Univ, Sch Pharm, Shenyang 110001, Liaoning, Peoples R China

[3] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA

[4] Beckman Res Inst City Hope, Dept Mol Med, Duarte, CA 91010 USA

[5] City Hope Med Ctr, Beckman Res Inst, Integrat Genom Core, Duarte, CA 91010 USA

[6] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[7] Beckman Res Inst City Hope, Dept Hematol Malignancies Translat Sci, Monrovia, CA 91016 USA

[8] City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA 91010 USA

[9] City Hope Natl Med Ctr, City Hope Comprehens Canc Ctr, Duarte, CA 91010 USA

[10] City Hope Natl Med Ctr, Gehr Family Ctr Leukemia Res, Duarte, CA 91010 USA

[11] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Radiat Oncol, Guangzhou 510080, Guangdong, Peoples R China

[12] Tianjin Univ, Sch Pharmaceut Sci & Technol, Tianjin Key Lab Modern Drug Delivery & High Effic, Tianjin 300072, Peoples R China

[13] Tianjin Univ, Collaborat Innovat Ctr Chem Sci & Engn Tianjin, Tianjin 300072, Peoples R China

[14] Houston Methodist, Dept Pathol & Genom Med, Houston, TX 77030 USA

[15] Zhejiang Univ, Affiliated Hosp 1, Dept Hematol, Hangzhou 31003, Zhejiang, Peoples R China

[16] Midwestern Univ, Coll Pharm Glendale, Dept Pharmaceut Sci, Glendale, AZ 85308 USA

[17] Harvard Med Sch, Ctr Canc, Massachusetts Gen Hosp, Boston, MA 02114 USA

[18] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Liver Surg, Shanghai 200127, Peoples R China

来源：

CANCER CELL | 2020年 / 38卷 / 01期

基金：

美国国家卫生研究院;

关键词：

OBESITY-ASSOCIATED PROTEIN; PHASE-I; MYELOID-LEUKEMIA; FAT MASS; RNA DEMETHYLASE; BISANTRENE; DRUG; EXPRESSION; NSC-368390; PROMOTES;

D O I：

10.1016/j.ccell.2020.04.017

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Fat mass and obesity-associated protein (FTO), an RNA N-6-methyladenosine (m(6)A) 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.

引用

页码：79 / +

页数：29

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