Differential Regulation of Cancer Progression by CDK4/6 Plays a Central Role in DNA Replication and Repair Pathways

Abstract Although the cyclin-dependent kinases CDK4 and CDK6 play fundamental roles in cancer, specific pathways downstream targets by which they exert their tumorigenic effects remain elusive. In this study, we uncover distinct novel functions for these regulating tumor formation metastatic colonization various solid tumors, including those of breast, prostate, pancreas. Combining vivo CRISPR-based gene editing with pharmacologic inhibition approaches orthotopic transplantation patient-derived xenograft preclinical models, defined clear facilitating growth progression cancers. Transcriptomic profiling CDK4/6 CRISPR knockouts breast cancer revealed two to regulate through mechanisms. regulated prometastatic inflammatory cytokine signaling, whereas mainly controlled DNA replication repair processes. Inhibition but not resulted defective increased damage. Multiple replication/repair genes were only associated subtype, grades, poor clinical outcomes, also facilitated primary metastasis vivo. genomic deletion efficiently blocked preestablished cell- models providing a potential targeted therapy deadly tumors. Significance: In-depth transcriptomic analysis identifies as regulators signaling reveals pathway central promoting effects.