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

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

Authors:	Gleason, C. E.; Dickson, M. A.; Klein, M. E.; Antonescu, C. R.; Gularte-Mérida, R.; Benitez, M.; Delgado, J. I.; Kataru, R. P.; Tan, M. W. Y.; Bradic, M.; Adamson, T. E.; Seier, K.; Richards, A. L.; Palafox, M.; Chan, E.; D'Angelo, S. P.; Gounder, M. M.; Keohan, M. L.; Kelly, C. M.; Chi, P.; Movva, S.; Landa, J.; Crago, A. M.; Donoghue, M. T. A.; Qin, L. X.; Serra, V.; Turkekul, M.; Barlas, A.; Firester, D. M.; Manova-Todorova, K.; Mehrara, B. J.; Kovatcheva, M.; Tan, N. S.; Singer, S.; Tap, W. D.; Koff, A.
Article Title:	Therapy-induced senescence contributes to the efficacy of abemaciclib in patients with dedifferentiated liposarcoma
Abstract:	Purpose: 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 inflammationprovoking 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 inDDLS. The discovery ofANGPTL4 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. © 2023 The Authors.
Keywords:	immunohistochemistry; controlled study; human cell; phenotype; phase 2 clinical trial; gene amplification; pathology; real time polymerase chain reaction; dna microarray; doxycycline; transcriptome; cell aging; benzimidazole derivative; benzimidazoles; liposarcoma; cyclin dependent kinase 4; cyclin-dependent kinase 4; tumor microenvironment; rna isolation; principal component analysis; gene ontology; cellular senescence; dedifferentiated liposarcoma; humans; human; article; palbociclib; rna sequencing; abemaciclib; aminopyridines; aminopyridine derivative; gene set enrichment analysis; a-549 cell line; huh-7 cell line
Journal Title:	Clinical Cancer Research
Volume:	30
Issue:	4
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2024-02-15
Start Page:	703
End Page:	718
Language:	English
DOI:	10.1158/1078-0432.Ccr-23-2378
PUBMED:	37695642
PROVIDER:	scopus
PMCID:	PMC10870201
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85185220802&doi=10.1158%2f1078-0432.CCR-23-2378&partnerID=40&md5=67a45c5401a8ea61c8c47c575e6c49ac
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding authors are Andrew Koff and William Tap -- Source: Scopus