MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer

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.

Automated summary

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.