Data from Therapy-Induced Senescence Contributes to the Efficacy of Abemaciclib in Patients with Dedifferentiated Liposarcoma

Afsar Barlas,Aimee M Crago,Allison L Richards,Andrew Koff,Babak J Mehrara,Caroline E Gleason,Ciara M Kelly,Cristina R Antonescu,Daniel M Firester,Eric Chan,Jonathan Landa,Juliana I Delgado,Katia Manova-Todorova,Kenneth Seier,Li-Xuan Qin,Marimar Benitez,Mark A Dickson,Mark T.A Donoghue,Mark Wei Yi Tan,Marta Kovatcheva,Marta Palafox,Martina Bradic,Mary E Klein (Dooley),Mary Louise Keohan,Mesruh Turkekul,Mrinal M Gounder,Nguan Soon Tan,Ping Chi,Raghu P Kataru,Rodrigo Gularte-Mérida,Samuel Singer,Sandra P D'Angelo,Sujana Movva,Travis E Adamson,Violetta Serra,William D Tap

doi:10.1158/1078-0432.c.7077823

Abstract

<div>AbstractPurpose:We conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in the preclinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans.Patients and Methods: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 200 mg 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 tumor cell 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 also more likely to acquire resistance later in therapy. These suggest that combining senolytics with abemaciclib in a subset of patients may improve the duration 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 CDK4/6i-induced cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes.<a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-2787" target="_blank">See related commentary by Weiss et al., p. 649</a></div>

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