Therapy-induced senescence contributes to the efficacy of abemaciclib in patients with dedifferentiated liposarcoma
Current research on CDK4/6 inhibitors (CDK4/6i) in the pre-clinical and clinical spaces are largely concerned with gaining a deeper understanding of how these drugs delay tumor growth, and how to prevent cancer cell resistance.  By coordinating a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies to identify the molecular basis of geroconversion, we have defined how therapy induced senescence contributes to disease management.  Thirty patients with progressing DDLS enrolled in the clinical trial and were treated with 200mg 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%).  ANGPTL4 is a necessary late regulator of geroconversion, the pathway from reversible cell cycle exit to a stably arrested inflammation-provoking senescent cell, in liposarcoma cell lines treated with CDK4/6i.  Using ANGPTL4 and CDKN2A expression, we were able to identify patients in which abemaciclib induced tumor cell senescence. We were then able to correlate this with outcomes. Senesence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy, and possibly with an improved initial response to abemaciclib.  However, those individuals with both senescence and increased TILs were also more likely to acquire resistance after six months of therapy.  This suggests that combining senolytics with abemaciclib in a subset of patients may improve the durability of patient responses to this class of compounds. Overall design: Two to three independent biological replicates of genetically engineered LS8817 cells were made to arrest in quiescence following doxyxyline and palbociclib treatment and  released from this arrest to progress synchronously into senesecence.  Samples were obtained over the next 28 days, RNA prepared, and correlated to the appearance of different phenotypes associated with senescence.