Abstract IA026: Epigenetic and genomic features define distinct cellular states with possible therapeutic relevance in osteosarcoma

Abstract

Abstract The Osteosarcoma (OS) genome is characterized by aneuploidy and dramatic structural rearrangements often leading to copy number gain and loss. Currently, all patients with osteoblastic OS at diagnosis are treated with the same highly toxic chemotherapy and no clinically relevant subtypes have been identified. While there is significant heterogeneity at the genome level between patients, less is known regarding epigenetic heterogeneity and how this may impact critical phenotypes such as therapy response and metastasis. To characterize the osteosarcoma epigenome, we integrated ATAC-seq and RNA-seq across a unique set of patient samples, PDXs and PDX-derived cell lines obtained across the disease continuum and including biopsies, resections, and metastasis. ATACseq analysis revealed the presence of two distinct epigenetic cell states (C1 and C2). Associating the differential genomic regions to likely regulated genes, the enriched pathways of Cluster 1 (C1) are related to mesenchymal cell proliferation, skeletal system morphogenesis, osteoblast differentiation, and Wnt signaling pathway. In contrast, Cluster 2 (C2) enriched pathways are related to cell motility and migration, extracellular matrix organization and regulation of protein serine/threonine kinase activity. Furthermore, accessible chromatin regions were enriched for a distinct set of transcription factor binding sites. We then assessed whether these epigenetic states were associated with response to targeted therapies. We identified unique vulnerability of C1 cell lines to AURK inhibitors whereas C2 cell lines had evidence for upregulation of MAPK and were vulnerable to treatment with trametinib. ATACseq analysis of PDX and a limited number of patient samples confirmed that these subtypes of OS also likely exist in patient tumors. In parallel to these studies, we have also carried out extensive additional analysis of vulnerability of OS cell ines to a wide range of targeted therapies. We find evidence for significant response to several inhibitors of the ATR-WEE1-CHK1 pathway nominating this as a potential novel vulnerability for OS. Therapeutic relevance of these findings is currently being explores in an orthotopic metastasis model of OS. Overall, our findings may define new subtypes of osteosarcoma with unique therapeutic vulnerabilities. Citation Format: E. Alejandro Sweet-Cordero. Epigenetic and genomic features define distinct cellular states with possible therapeutic relevance in osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA026.