Dual targeting of conserved cell cycle and transcription programs in advanced colorectal cancer by fadraciclib.

BACKGROUND AND OBJECTIVES: Control of cell division is tightly regulated in eukaryotic cells, and dysfunction in cell cycle checkpoints is a key hallmark of malignant transformation that promotes a fitness advantage over non-cancer cells. One of the most critical mechanisms of cell cycle regulation is via the cyclin-dependent kinases (CDKs), which connect resource availability sensing and growth signaling with cell division and transcription elongation processes. Novel combination therapy approaches to co-target cell cycle and transcriptional CDKs may improve cancer-specific targeting of CDK dysfunction. In the current study, we assessed the effectiveness of fadraciclib, a new CDK2/9 inhibitor, for the treatment of advanced colorectal cancer (CRC). METHODOLOGY: A panel of eighteen CRC patient-derived organoids (PDOs) was used to assess the efficacy of fadraciclib. Efficacy was further validated in patient-derived xenografts (PDXs). CDK2/9 target inhibition, cell cycle arrest, and cell killing mechanisms were investigated using western blotting, flow cytometry, and immunofluorescence staining, respectively. RESULTS: CRC PDOs exhibited greater sensitivity to fadraciclib compared to chemotherapy and palbociclib. This efficacy was validated in vivo using three matched PDXs, showing significant tumor growth inhibition with fadraciclib compared to vehicle (P < .05) and no serious adverse effects. Fadraciclib induced G2/M cell cycle arrest, leading to multipolar mitosis and anaphase catastrophe. CONCLUSIONS AND IMPLICATIONS: Our results using patient-derived models suggest that fadraciclib is a promising therapy for advanced CRC by inhibiting CDKs 2 and 9, which affects critical pathways in cell cycle regulation and transcription.