| Literature DB >> 36150391 |
Shunsuke Kitajima1, Tetsuo Tani2, Benjamin F Springer3, Marco Campisi2, Tatsuya Osaki4, Koji Haratani2, Minyue Chen5, Erik H Knelson2, Navin R Mahadevan6, Jessica Ritter7, Ryohei Yoshida2, Jens Köhler2, Atsuko Ogino2, Ryu-Suke Nozawa8, Shriram K Sundararaman9, Tran C Thai2, Mizuki Homme10, Brandon Piel2, Sophie Kivlehan11, Bonje N Obua11, Connor Purcell12, Mamiko Yajima13, Thanh U Barbie14, Patrick H Lizotte11, Pasi A Jänne2, Cloud P Paweletz11, Prafulla C Gokhale3, David A Barbie15.
Abstract
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 transient 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 followed 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.Entities:
Keywords: 2’3’-cGAMP; DNMT1; EZH2; KRAS-LKB1 mutant lung adenocarcinoma; STING; cGAS; monopolar spindle kinase 1
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Year: 2022 PMID： 36150391 PMCID： PMC9561026 DOI： 10.1016/j.ccell.2022.08.015
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 38.585