The low-dose CHK1 inhibitor prexasertib triggers VDAC1 dephosphorylation to activate mtDNA-STING signaling and synergize immunotherapy
Summary: CHK1 inhibitors exhibit dose-limiting toxicity despite potent tumor cytotoxicity in clinical trials. Here, we reveal that low-dose prexasertib induces mtDNA damage by impairing repair machinery, triggering cytosolic mtDNA release via VDAC1 to activate STING-mediated innate immunity. Mechani...
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| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-05-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725003766 |
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| Summary: | Summary: CHK1 inhibitors exhibit dose-limiting toxicity despite potent tumor cytotoxicity in clinical trials. Here, we reveal that low-dose prexasertib induces mtDNA damage by impairing repair machinery, triggering cytosolic mtDNA release via VDAC1 to activate STING-mediated innate immunity. Mechanistically, prexasertib blocks CHK1 phosphorylation and competitively recruits Nek1 kinase, thereby activating the ATR/CHK1 signaling cascade. Consequently, it disrupts the phosphorylation of VDAC1 by Nek1 kinase at T107 and promotes the formation of VDAC1 oligomers, where mtDNA exits. In vivo, low-dose prexasertib exhibits immune-modulatory effects and synergizes safely with immune checkpoint blockade at subtherapeutic doses. Our findings establish reduced-dose CHK1 inhibition as a strategy to amplify immunotherapy efficacy while circumventing systemic toxicity, providing a translatable framework for optimizing therapeutic windows in clinical oncology. |
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| ISSN: | 2211-1247 |