Inhibition of G Protein–Coupled Receptor Kinase 2 Promotes Unbiased Downregulation of IGF1 Receptor and Restrains Malignant Cell Growth

Abstract The ability of a receptor to preferentially activate only subset available downstream signal cascades is termed biased signaling. Although comprehensively recognized for the G protein–coupled receptors (GPCR), this process scarcely explored tyrosine kinases (RTK), including cancer-relevant insulin-like growth factor-1 (IGF1R). Successful IGF1R targeting requires downregulation, yet therapy-mediated removal from cell surface activates cancer-protective ?-arrestin–biased signaling (?-arr-BS). As these overlapping processes are initiated by ?-arr/IGF1R interaction and controlled GPCR-kinases (GRK), we GRKs as potential anticancer therapeutic targets disconnect downregulation ?-arr-BS. Transgenic modulation demonstrated that GRK2 inhibition or GRK6 overexpression enhanced degradation IGF1R, but both scenarios sustained IGF1–induced Pharmacologic clinically approved antidepressant, serotonin reuptake inhibitor paroxetine (PX), recapitulated effects silencing with dose- time-dependent without associated In vivo, PX treatment caused substantial suppressing Ewing's sarcoma xenografts. Functional studies reveal exploits antagonism between ?-arrestin isoforms; in low ligand conditions, favored ?-arrestin1/Mdm2-mediated ubiquitination/degradation scenario usually exclusive abundancy, making more effective than antibody-mediated downregulation. This study provides rationale, molecular mechanism, validation feasible concept “system bias” uncouple Demonstrating system bias an approach, our reveals novel strategy rational design repurposing therapeutics selectively cross-target other RTK. Significance: work insight into biological roles RTK increase efficacy anti–IGF1R-targeted therapy cancer.