MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer
Menée à l'aide de lignées cellulaires et de modèles murins, cette étude démontre que l'inhibition de la kinase MPS1 améliore l'immunogénicité des cancers du poumon avec mutation KRAS-LKB1
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.
Cancer Cell 2022