||Tuesday, 7 March 2023, 16:00～17:00
||International Conference Room, Center for Smart-Aging Research, 1F (IDAC), Web
||Novel strategy for priming immunogenicity through STING activation following MPS1 inhibition
||Department of Cell Biology, Japanese Foundation for Cancer Research
||Kozo Tanaka (Department of Molecular Oncology, ext 8491)
||Despite the impressive efficacy of PD-(L)1 blockade in lung cancer, specific genomic subsets promote intrinsic resistance. KRAS-LKB1 (KL) mutant lung cancers silence STING in an epigenetic manner, resulting in T cell exclusion and resistance to PD-(L)1 blockade. Here we discover that KL cells also minimize intracellular accumulation of 2’3’-cGAMP to further avoid downstream STING activation. An unbiased screen to co-opt this vulnerability reveals that transient MPS1 inhibition potently re-engages this pathway in KL cells via micronuclei generation. This strategy primarily impacts dividing cells, targets a major underlying mechanism of KL tumor immune escape, and involves pulse scheduling of inhibitors undergoing clinical development, facilitating translation into human trials.