Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

被引：11

作者：

Wu, Meng-Ju ^{[1
,2
,3
,4
]}

Kondo, Hiroshi ^{[1
,2
,3
,4
]}

Kammula, Ashwin V. ^{[1
,3
,4
]}

Shi, Lei ^{[1
,2
,3
,4
]}

Xiao, Yi ^{[5
]}

Dhiab, Sofiene ^{[1
,2
,3
,4
]}

Xu, Qin ^{[1
,2
,3
,4
]}

Slater, Chloe J. ^{[1
,2
,3
,6
,7
]}

Avila, Omar I. ^{[1
,3
,4
]}

Merritt, Joshua ^{[1
,2
,3
,4
]}

Kato, Hiroyuki ^{[1
,2
,3
,4
]}

Kattel, Prabhat ^{[1
,2
,3
,4
]}

Sussman, Jonathan ^{[8
,9
,10
]}

Gritti, Ilaria ^{[1
,2
,3
,4
]}

Eccleston, Jason ^{[8
,9
]}

Sun, Yi ^{[1
]}

Cho, Hyo Min ^{[1
,2
,3
,4
]}

Olander, Kira ^{[4
]}

Katsuda, Takeshi ^{[8
,9
]}

Shi, Diana D. ^{[5
,11
]}

Savani, Milan R. ^{[5
,12
]}

Smith, Bailey C. ^{[5
]}

Cleary, James M. ^{[13
]}

Mostoslavsky, Raul ^{[1
,2
,3
,4
]}

Vijay, Vindhya ^{[1
,2
,3
,4
]}

Kitagawa, Yosuke ^{[14
]}

Wakimoto, Hiroaki ^{[14
]}

Jenkins, Russell W. ^{[1
,3
,4
,15
]}

Yates, Kathleen B. ^{[1
,3
,4
]}

Paik, Jihye ^{[16
]}

Tassinari, Ania ^{[7
]}

Saatcioglu, Duygu Hatice ^{[7
]}

Tron, Adriana E. ^{[7
]}

Haas, Wilhelm ^{[1
,3
,4
]}

Cahill, Daniel ^{[14
]}

Mcbrayer, Samuel K. ^{[5
,17
]}

Manguso, Robert T. ^{[1
,3
,4
]}

Bardeesy, Nabeel ^{[1
,2
,3
,4
]}

机构：

[1] Massachusetts Gen Hosp, Krantz Family Ctr Canc Res, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA

[3] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[4] Massachusetts Inst Technol & Harvard, Broad Inst, Cambridge, MA 02139 USA

[5] Univ Texas Southwestern Med Ctr Dallas, Childrens Med Ctr Res Inst, Dallas, TX USA

[6] Univ Paris Saclay, Inst Gustave Roussy, INSERM, U1015, Villejuif, France

[7] Servier Pharmaceut LLC, Boston, MA USA

[8] Univ Penn, Perelman Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA USA

[9] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA USA

[10] Univ Penn, Perelman Sch Med, Grad Grp Genom & Computat Biol, Philadelphia, PA USA

[11] Harvard Med Sch, Dept Radiat Oncol, Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02115 USA

[12] Univ Texas Southwestern Med Ctr, Med Scientist Training Program, Dallas, TX USA

[13] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Div Gastrointestinal Oncol, Boston, MA USA

[14] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA USA

[15] Harvard Med Sch, Harvard Program Therapeut Sci, Lab Syst Pharmacol, Boston, MA USA

[16] Cornell Univ, Weill Med Coll, Sandra & Edward Meyer Canc Ctr, Dept Pathol & Lab Med, New York, NY USA

[17] Univ Texas SouthWestern Med Ctr Dallas, Dept Pediat, Dallas, TX USA

来源：

SCIENCE | 2024年 / 385卷 / 6705期

基金：

美国国家卫生研究院; 日本学术振兴会;

关键词：

DIFFERENTIAL EXPRESSION ANALYSIS; REVERSE-TRANSCRIPTASE; ENDOGENOUS RETROVIRUSES; TRANSPOSABLE ELEMENTS; CELL-LINE; MUTATIONS; CANCER; (R)-2-HYDROXYGLUTARATE; IDENTIFICATION; MAINTENANCE;

D O I：

10.1126/science.adl6173

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores antitumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase (TE-RT) activates cGAS, triggering viral mimicry and stimulating antitumor immunity. In summary, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous RT activity to the mechanism of action of a US Food and Drug Administration-approved oncology drug.

引用

页数：20

共 50 条

[21] Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors
Sule, Amrita
Van Doorn, Jinny
Sundaram, Ranjini K.
Ganesa, Sachita
Vasquez, Juan C.
Bindra, Ranjit S.
NAR CANCER, 2021, 3 (02):
[22] Mutant IDH1 inhibitors activate pSTAT3-Y705 leading to an increase in BCAT1 and YKL-40 levels in mutant IDH1-expressing cells
Bhattacharjee, Debanjan
Balabhaskararao, Kancharana
Jain, Nishant
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2021, 1868 (11):
[23] Plk1 regulates mutant IDH1 enzyme activity and mutant IDH2 ubiquitination in mitosis
Reddy, M. Saikiran
Bhattacharjee, Debanjan
Jain, Nishant
CELLULAR SIGNALLING, 2022, 92
[24] Recent advances of IDH1 mutant inhibitor in cancer therapy
Tian, Wangqi
Zhang, Weitong
Wang, Yifan
Jin, Ruyi
Wang, Yuwei
Guo, Hui
Tang, Yuping
Yao, Xiaojun
FRONTIERS IN PHARMACOLOGY, 2022, 13
[25] Altered cancer cell metabolism in gliomas with mutant IDH1 or IDH2
Borodovsky, Alexandra
Seltzer, Meghan J.
Riggins, Gregory J.
CURRENT OPINION IN ONCOLOGY, 2012, 24 (01) : 83 - 89
[26] Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma
Nakagawa, Makoto
Nakatani, Fumihiko
Matsunaga, Hironori
Seki, Takahiko
Endo, Makoto
Ogawara, Yoko
Machida, Yukino
Katsumoto, Takuo
Yamagata, Kazutsune
Hattori, Ayuna
Fujita, Shuhei
Aikawa, Yukiko
Ishikawa, Takamasa
Soga, Tomoyoshi
Kawai, Akira
Chuman, Hirokazu
Yokoyama, Nobuhiko
Fukushima, Suguru
Yahiro, Kenichiro
Kimura, Atsushi
Shimada, Eijiro
Hirose, Takeshi
Fujiwara, Toshifumi
Setsu, Nokitaka
Matsumoto, Yoshihiro
Iwamoto, Yukihide
Nakashima, Yasuharu
Kitabayashi, Issay
ONCOGENE, 2019, 38 (42) : 6835 - 6849
[27] Structure-based discovery of IHMT-IDH1-053 as a potent irreversible IDH1 mutant selective inhibitor
Liang, Qianmao
Wang, Beilei
Zou, Fengming
Guo, Gongrui
Wang, Wenliang
Wang, Wei
Liu, Qingwang
Shen, Lijuan
Hu, Chen
Wang, Wenchao
Wang, Aoli
Huang, Tao
He, Yuying
Xia, Ruixiang
Ge, Jian
Liu, Jing
Liu, Qingsong
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2023, 256
[28] Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo
Popovici-Muller, Janeta
Saunders, Jeffrey O.
Salituro, Francesco G.
Travins, Jeremy M.
Yan, Shunqi
Zhao, Fang
Gross, Stefan
Dang, Lenny
Yen, Katharine E.
Yang, Hua
Straley, Kimberly S.
Jin, Shengfang
Kunii, Kaiko
Fantin, Valeria R.
Zhang, Shunan
Pan, Qiongqun
Shi, Derek
Biller, Scott A.
Su, Shinsan M.
ACS MEDICINAL CHEMISTRY LETTERS, 2012, 3 (10): : 850 - 855
[29] An olive oil phenolic is a new chemotype of mutant isocitrate dehydrogenase 1 (IDH1) inhibitors
Verdura, Sara
Cuyas, Elisabet
Lozano-Sanchez, Jesus
Bastidas-Velez, Cristian
Llorach-Pares, Laura
Fernandez-Arroyo, Salvador
Hernandez-Aguilera, Anna
Joven, Jorge
Nonell-Canals, Alfons
Bosch-Barrera, Joaquim
Martin-Castillo, Begona
Vellon, Luciano
Sanchez-Martinez, Melchor
Segura-Carretero, Antonio
Menendez, Javier A.
CARCINOGENESIS, 2019, 40 (01) : 27 - 40
[30] Evaluation of IDH1 status in diffusely infiltrating gliomas by immunohistochemistry using anti-mutant and wild type IDH1 antibodies
Ikota, Hayato
Nobusawa, Sumihito
Arai, Hideo
Kato, Yukinari
Ishizawa, Keisuke
Hirose, Takanori
Yokoo, Hideaki
BRAIN TUMOR PATHOLOGY, 2015, 32 (04) : 237 - 244

← 1 2 3 4 5 →