MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer

Cancer Cell. 2022 Oct 10;40(10):1128-1144.e8. doi: 10.1016/j.ccell.2022.08.015. Epub 2022 Sep 22.


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.

Keywords: 2’3’-cGAMP; DNMT1; EZH2; KRAS-LKB1 mutant lung adenocarcinoma; STING; cGAS; monopolar spindle kinase 1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Decitabine
  • Genes, ras
  • Humans
  • Ligands
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Proto-Oncogene Proteins p21(ras)* / genetics
  • Proto-Oncogene Proteins p21(ras)* / metabolism


  • KRAS protein, human
  • Ligands
  • Decitabine
  • Proto-Oncogene Proteins p21(ras)