Abstract 2954: Chromatin accessibility dynamics in CDK4/6 inhibitor-induced senescence

Abstract

Abstract Liposarcomas are a rare cancer that often undergo amplification of the 12q13-15 locus, which includes the gene encoding the cyclin-dependent kinase CDK4; CDK4/6 inhibitors therefore offer a promising targeted therapy to halt proliferation in these tumors where therapeutic options are scarce once surgical resection is no longer possible. CDK4/6 inhibition can lead to either reversible or irreversible exit from the cell cycle (quiescence or senescence, respectively), but the underlying mechanisms are not well understood. Applying ATAC-seq in a liposarcoma cell line model of therapy-induced senescence, we have assayed alterations in the chromatin landscape that arise in response to CDK4/6 inhibitor treatment to identify epigenetic changes that drive this cell fate decision. Additionally, we have compared this with cells that undergo senescence due to DNA damage induced by the drug doxorubicin, an anthracycline that is the standard first-line chemotherapy for liposarcoma. In CDK4/6 inhibition, we identified dynamic patterns of accessibility as cells transition from quiescence to senescence over 28 days of treatment. NF-kB motifs in promoter-proximal regions displayed increased accessibility as cells commit to the senescence state, and ATAC-seq peaks with AP-1 transcription factor family motifs exhibit dynamic accessibility. We characterized the DNA damage response by gamma-H2AX and 53BP1 immunofluorescence and found that for CDK4/6 inhibition there is minimal DNA damage and only at late senescence time points, in marked contrast with doxorubicin treatment. We observed differences in accessibility between CDK4/6 inhibitor- and doxorubicin-induced senescence in a region on chromosome 6 that contains the gene FRK. This gene encodes a tyrosine kinase in the Src family that negatively regulates cell proliferation and has been implicated as a tumor suppressor through upregulation of p21, which may reinforce restriction of phosphorylation on Rb in parallel with CDK4/6 inhibition. These findings provide further evidence of the epigenetic impact of CDK4/6 inhibitors in cancer cells, and highlight shared and specific mechanisms that lead to therapy-induced senescence. Citation Format: Justin Rendleman, Joanna Yeung, Nicole Pagane, Irene Duba, Andrew Scortea, Andrew Koff, Viviana I. Risca. Chromatin accessibility dynamics in CDK4/6 inhibitor-induced senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2954.