Perk mediates tumor cell fate and therapeutic outcome in response to CDK4/6 inhibition

Dysregulation of cyclin-dependent kinase 4/6 (CDK4/6) occurs in cancer and is targeted by CDK4/6 inhibitors (CDK4/6i) including palbociclib (PD). CDK4/6i triggers quiescence (reversible) which transitions to senescence (irreversible) following prolonged exposure. Resolving the program that directs this transition is critical to overcoming CDK4/6i resistance and improving the efficacy of CDK4/6 inhibitors. We demonstrate that CDK4/6i predominantly triggers PERK, a shared kinase between the unfolded protein response (UPR) and integrated stress response (ISR). Inhibition of PERK combined with CDK4/6i impairs UPR/ISR adaptive signaling instructing early commitment to senescence. Early senescence commitment reflects accelerated senescence markers, dephosphorylation of the Retinoblastoma (RB), and engagement of a senescence specific gene signature. Combined treatment with CDK4/6i and ISRIB (ISR inhibitor) reduces tumor growth more effectively than single agents through increased senescence and immune cell surveillance. This work highlights CDK4/6i+ISRIB as a potential therapy for a range of cancers with an intact CDK4/6-RB1 axis. CDK4/6 inhibitors can trigger stress responses that alter tumor outcomes. Here, the authors show that PERK signaling shapes cell fate after CDK4/6 inhibition and influences response to therapy.