Exploring Mechanism of Action of Abemaciclib in Breast Cancer Through Circulating Chromatin Fragment

Abstract Cell free DNA (cfDNA) analysis has a large potential for cancer patient diagnosis. Given the evidence that cfDNA partially preserves chromatin architecture of tumor cells, it potentially allows the detection of tumor responses after therapeutic treatment. In this study, we aimed to detect the responses of abemaciclib, a potent cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6 inhibitor), in metastatic recurrent breast cancer patients through cfDNA analysis. Our results suggest that cfDNA can be used as a valuable marker to monitor cancer burden, cancer responses to drug treatment, and sensitivity against therapeutic reagents. CfDNA concentrations purified from serum are significantly higher in cancer patients compared to healthy donors, suggesting that a significant portion of the cfDNA originates from tumors in our samples. The cfDNA concentrations are also significantly decreased after abemaciclib treatment. The sequencing analysis of cfDNAs revealed a higher enrichment of cfDNAs at open chromatin regions and differentiated the cfDNA enrichment patterns between abemaciclib treated and non-treated samples. Altered cfDNA signals are frequently associated with the genes that are involved in apoptosis and CDK4/6 related pathways. Finally, the differentially enriched region analysis also detected the differences in abemaciclib cases that could be treated long-term and cases that had an exacerbation after short-term treatment. In conclusion, this research enhances our understanding of the biology of abemaciclib and provides new insights into CDK4/6 inhibitor’s action in metastatic breast cancer.