Mitochondrial damage triggers therapy-induced senescence

Glioblastoma (GBM) is a fatal brain tumor with a critical need for better therapies. It is known that the PI3K, MAPK, and CDK4/6 signaling pathways are hyper-activated in these tumors; however, previous studies have used very high concentration of inhibitors to assess their importance, with mixed results. Here we developed PMCi, a combination approach that targets all three pathways simultaneously, at clinically-relevant doses. PMCi effectively suppresses GBM cell proliferation in vitro and in vivo, and outperforms monotherapies and dual combinations. PMCi acts by inducing cellular senescence, which is mediated solely by the mitochondria, and, unlike other forms of senescence, is independent of nuclear damage. This phenotype is caused by a reactive oxygen species (ROS)\cGAS-STING\senescence-associated secretory phenotype (SASP) signaling cascade, that acts in a paracrine manner to establish and maintain senescence. Our results demonstrate that mitochondrial damage is sufficient to drive senescence, and that this can be leveraged to target GBM cells.