Journal
CANCER CELL
Volume 40, Issue 10, Pages 1128-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2022.08.015
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Funding
- NCI Cancer Center Support Grant [NsluIH 5 P30 CA06516]
- NIH [R01CA190294]
- Ludwig Center at Harvard Medical School
- Mark Foundation
- Heerwagen, Candice Bagby, Ming and Polly Tsai Funds for Lung Cancer Research
- DFCI/Northeastern University Joint Program in Cancer Drug Development
- JSPS Postdoctoral Fellowship for Research Abroad
- Developmental Research Project Award in Lung Cancer Research
- program of Leading Initiative for Excellent Young Researchers
- JSPS KAKENHI [20H03521]
- AMED P-CREATE [20cm0106705h0001, 21cm0106705h0002]
- Takeda Science Foundation
- Princess Takamatsu Cancer Research Fund
- Uehara Memorial Foundation Research Fellowship
- Lilly Oncology Fellowship Program
- AIRC fellowship for Abroad
- Gross-Loh Fellowship
- Expect Miracles Foundation
- Robert A. and Renee E. Belfer Family Foundation
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KRAS-LKB1 mutant lung cancers silence the STING pathway and minimize intracellular accumulation of 2'3'-cGAMP to avoid T cell infiltration and decrease response to PD-1 blockade. However, transient MPS1 inhibition can re-activate the STING pathway in KL cells and restore T cell infiltration, enhancing the efficacy of anti-PD-1 treatment.
KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T cell exclusion and resistance to programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL cells also minimize intracellular accumulation of 2'3'-cyclic GMP-AMP (2'3'-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased screen to co-opt this vulnerability reveals that tran-sient MPS1 inhibition (MPS1i) potently re-engages this pathway in KL cells via micronuclei generation. This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment fol-lowed by pulse MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity.
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