Abstract 367: Temporal dynamics of the senescence-associated secretory phenotype triggered by CDK4/6 inhibitor or doxorubicin treatment in liposarcoma

Abstract Liposarcoma is a rare cancer that frequently exhibits amplification of the cyclin-dependent kinase CDK4 gene. CDK4/6 inhibitors (CDK4/6i) represent a promising targeted therapy to halt proliferation in these tumors, particularly when therapeutic options are limited, and surgical resection is no longer viable. CDK4/6 inhibition can result in either reversible or irreversible exit from the cell cycle (quiescence or senescence, respectively), but the mechanisms driving these outcomes remain unclear. Since CDK4/6 inhibitors appear to induce cell cycle arrest without causing extensive DNA damage, we hypothesize that the senescence-associated secretory phenotype (SASP)—a collection of secreted proinflammatory molecules—induced by CDK4/6i differs significantly from the SASP triggered by cytotoxic chemotherapeutics such as doxorubicin. To investigate this, we characterized differences in SASP gene expression and its upstream regulators using RNA-seq and ATAC-seq in a 28 day time-course study of a patient-derived liposarcoma cell line responsive to both drugs. Our findings reveal that extracellular matrix (ECM) genes are upregulated early in CDK4/6i treatment, a response largely absent in doxorubicin-treated cells. Many of these ECM genes are previously identified SASP components, suggesting a CDK4/6i-specific SASP module. We identified the Hippo pathway regulator TEAD as a key player in shaping this response. Pharmacological inhibition of TEAD suppresses the upregulation of key SASP genes, ANGPTL4 and IGFBP3, which are more strongly induced by CDK4/6i compared to doxorubicin. While the SASP profiles differ between drugs early in treatment, we observe emergence of a shared SASP signature characterized by NF-κB signaling at later time points. This is indicated by upregulation of NF-κB target genes and enrichment of NF-κB motifs in the regions with increased chromatin accessibility under both drugs. In both cases, we detect increased nuclear localization of p65, a subunit of NF-κB, confirming NF-κB activation. Furthermore, addition of an NF-κB inhibitor suppresses the upregulation of NF-κB target SASP genes in both treatments. These results highlight how the composition of therapy-induced SASP evolves over time and contains both common and treatment-specific modules. We also demonstrate that NF-κB activity contributes to shaping part of the CDK4/6i-induced senescence response, addressing an area of ongoing debate in the field. Our study provides new insights into how cancer therapies regulate the SASP profile, with implications for understanding the effects of therapy-induced senescence on the tumor microenvironment. Citation Format: Joanna Lan Hing Yeung, Justin Rendleman, Nicole Pagane, Irene Duba, Andrew Scortea, Lauren Anderson, Ria Hosuru, Bat Ider Tumenbayar, Andrew Koff, Viviana Risca. Temporal dynamics of the senescence-associated secretory phenotype triggered by CDK4/6 inhibitor or doxorubicin treatment in liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 367.