Therapy-induced senescence contributes to the efficacy of abemaciclib in patients with dedifferentiated liposarcoma.

Overview

abstract

PURPOSE: We conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in both the pre-clinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans. EXPERIMENTAL DESIGN: We coordinated a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies interrogating the molecular basis of geroconversion. RESULTS: Thirty patients with progressing DDLS enrolled and were treated with 200mg of abemaciclib twice daily. The median progression free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI 57.7% - 90.1%). No new safety signals were identified. Concurrent preclinical work in liposarcoma cell lines identified ANGPTL4 as a necessary late regulator of geroconversion, the pathway from reversible cell cycle exit to a stably arrested inflammation-provoking senescent cell. Using this insight we were able to identify patients in which abemaciclib induced senescence. Senescence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy. However, those individuals with both senescence and increased TILs were more likely to acquire resistance later in therapy. This suggests that combining senolytics with abemaciclib in a subset of patients may improve the duratiion of response. CONCLUSIONS: Abemaciclib was well tolerated and showed promising activity in DDLS. The discovery of ANGPTL4 as a late regulator of geroconversion helped to define how cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes.