Identification of a Conserved Temporal Molecular Response Signature to CDK4/6 Inhibition Through Multi-Omics Integration Across Cancer Cell Lines

Treatment of metastatic breast cancer with CDK4/6 inhibitors in combination with hormone ablation is the current first-line standard of care for this indication, and the therapeutic activity of these inhibitors has been demonstrated in various tumor entities. However, the efficacy of CDK4/6 inhibitor monotherapy is limited and requires combination with suitable additional inhibitors. Delineating the molecular pathways underlying treatment response may provide a rationale for personalized combination therapies that target deregulated pathways upstream of the core signature of response. We applied a comprehensive cross-omics approach to identify a conserved molecular response to CDK4/6 inhibition. Integration of transcriptomic, proteomic, and functional genomic data across multiple cancer models enabled us to refine a previously proposed multi-step model of response to the CDK4/6 inhibitor palbociclib. Initiation of cell-cycle arrest and inhibition of DNA replication is followed by activation of signaling events that suppress mitotic transcriptional programs. The identified panel of highly conserved candidate biomarkers warrants future experimental and clinical validation.