(P 11) GENETIC AND EPIGENETIC CHARACTERIZATION OF SARCOMA STEM CELLS ACROSS SUBTYPES IDENTIFIES EZH2 AS A THERAPEUTIC TARGET

Objective: High-grade soft tissue sarcomas (STS) are heterogeneous and aggressive cancers that share a common treatment strategy comprising surgical resection, radiation, and chemotherapy. Disease progression on treatment is associated with poor patient outcomes. Recurrence and resistance to chemotherapy are significant barriers to improving patient survival. We identified a positive correlation between CSC abundance and doxorubicin IC50 in multiple resistant STS cell lines, and were thus interested in the contribution of STS cancer stem cells (STS-CSCs) to doxorubicin resistance. Specifically, we investigated if a common genetic signature across STS-CSCs could be targeted to improve the efficacy of existing treatment regimens.

Methods: STS-CTCs were isolated from human LPS, LMS, MFS, RMS, and UPS cell lines and analyzed by RNA-sequencing relative to the bulk population. Gene-set enrichment analysis of pathways upregulated in STS-CSCs identified Enhancer of Zeste homolog 2 (EZH2), a member of the polycomb repressive complex 2 (PRC2) responsible for H3K27 methylation as being enriched in the CSC population.

Results: Assay for Transposase Accessible Chromatin (ATAC-Seq) showed increased EZH2 activity and a shared epigenetic profile across subtypes. Targeting of EZH2 using the FDA-approved drug Tazemetostat specifically ablated the STS-CSC population. Treatment of doxorubicin resistant cell lines with tazemetostat resulted in a decrease in the STS-CSC population. Co-treatment with tazemetostat restored doxorubicin chemosensitivity in resistant lines.

Conclusion: These data confirm the presence of shared genetic programs across distinct subtypes of STS that are unique to CSCs and amenable to therapeutic targeting.