Abemaciclib is Active in Preclinical Models of Ewing's Sarcoma via Multi-pronged Regulation of Cell Cycle, DNA Methylation, and Interferon Pathway Signaling

Purpose: Ewing's sarcoma (ES) is a rare and highly malignant cancer that occurs in the bone and surrounding tissue of children and adolescents. The EWS/ETS fusion transcription factor that drives ES pathobiology was previously demonstrated to modulate cyclin D1 expression. In this study we evaluated abemaciclib, a small molecule CDK4 and CDK6 (CDK4 and 6) inhibitor currently under clinical investigation in pediatric solid tumors, in preclinical models of ES. Experimental Design: Using western blot, high content imaging, flow cytometry, ELISA, RNAseq, and CpG methylation assays, we characterized the in vitro response of ES cell lines to abemaciclib. We then evaluated abemaciclib in vivo in cell line-derived and patient-derived xenograft (CDX and PDX, respectively) mouse models of ES as either a monotherapy or in combination with chemotherapy. Results: Abemaciclib induced quiescence in ES cell lines via a G1 cell cycle block, characterized by decreased proliferation and reduction of Ki67 and FOXM1 expression and RB phosphorylation. In addition, abemaciclib reduced DNMT1 expression and promoted an inflammatory immune response as measured by cytokine secretion, antigen presentation, and interferon pathway upregulation. Single agent abemaciclib reduced ES tumor volume in preclinical mouse models and, when given in combination with doxorubicin or temozolomide plus irinotecan, durable disease control was observed. Conclusions: Collectively, our data demonstrate that the anti-tumor effects of abemaciclib in preclinical ES models are multifaceted and include cell cycle inhibition, DNA demethylation, and immunogenic changes.

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