期刊
CANCER DISCOVERY
卷 11, 期 5, 页码 1268-1285出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-20-1065
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资金
- Instituto de Salud Carlos III (FIS)
- FEDER (Spanish Ministry of Health) [PI19/00818, PI17/00411, PI17/02272, PI19/01352, PI17/00701, ERA-NET EPICA AC16/00041]
- CIBERONC [CB16/12/00489, CB16/12/00369, CB16/12/00443]
- CIBEROBN [CB12/03/30002]
- CIBERDEM [CB07/08/0014]
- CIBEREHD [CB06/04/0006]
- Spanish Ministry of Science and Innovation [RTI2018-101759-B-I00, PID2019-106982RB-I00, BFU201787958-P]
- Government of Navarra/FEDER [GNS2016-XA]
- FIS-Spanish Ministry of Health
- Fundacion Arnal Planelles
- Spanish Ministry of Science and Innovation
- AECC
- CIMA/University of Navarra
- PerMed 2019 MEET-AML
- MMRF 2017 Immunotherapy Program Grant Award
Epigenetic therapies induce viral mimicry in cancer cells, reshaping mitochondrial metabolism and driving caspase-independent tumor cell death, leading to increased sensitivity to BCL2 inhibitor drugs.
For millions of years, endogenous retroelements have remained transcriptionally silent within mammalian genomes by epigenetic mechanisms. Modern anticancer therapies targeting the epigenetic machinery awaken retroelement expression, inducing antiviral responses that eliminate tumors through mechanisms not completely understood. Here, we find that massive binding of epigenetically activated retroelements by RIG-I and MDA5 viral sensors promotes ATP hydrolysis and depletes intracellular energy, driving tumor killing independently of immune signaling. Energy depletion boosts compensatory ATP production by switching glycolysis to mitochondrial oxidative phosphorylation, thereby reversing the Warburg effect. However, hyperfunctional succinate dehydrogenase in mitochondrial electron transport chain generates excessive oxidative stress that unleashes RIP1-mediated necroptosis. To maintain ATP generation, hyperactive mitochondrial membrane blocks intrinsic apoptosis by increasing BCL2 dependency. Accordingly, drugs targeting BCL2 family proteins and epigenetic inhibitors yield synergistic responses in multiple cancer types. Thus, epigenetic therapy kills cancer cells by rewiring mitochondrial metabolism upon retroelement activation, which primes mitochondria to apoptosis by BH3-mimetics. SIGNIFICANCE: The state of viral mimicry induced by epigenetic therapies in cancer cells remodels mitochondrial metabolism and drives caspase-independent tumor cell death, which sensitizes to BCL2 inhibitor drugs. This novel mechanism underlies clinical efficacy of hypomethylating agents and venetoclax in acute myeloid leukemia, suggesting similar combination therapies for other incurable cancers.
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