(P 08) ELUCIDATING THE ROLE OF YAP IN SARCOMA DEVELOPMENT

Objective: High-grade complex karyotype sarcomas represent a rare and heterogeneous group of tumors. Despite their diverse histological subtypes and molecular profiles, these sarcomas are treated similarly with varying outcomes. Thus, identifying the factors driving high-grade complex karyotype sarcomas will create new targeted therapeutic opportunities.

Methods: Previously our lab developed a new preclinical model in which human mesenchymal stem cells (MSCs) can transform into multiple subtypes of complex karyotype sarcomas by knockout of the tumor suppressors RB and p53 and expression of an oncogene. Human RB-/-P53+/- MSCs with addition of Yes-associated protein (YAP), an oncogene driver, histologically and phenotypically reflects the most common sarcoma subtype in adults, undifferentiated pleomorphic sarcoma (UPS). Further, comparing differential expression analysis from YAP driven tumors and human UPS tumors from the cancer genome atlas (TCGA) revealed upregulation of oxidative phosphorylation pathways. In addition, genetic analysis of tumors formed by other oncogenes including PI3K, which forms osteosarcoma, revealed amplification of YAP. Therefore, we hypothesize that YAP is required for the development of soft tissue and bone sarcomas and serves as a viable therapeutic target for sarcomas.

Results: To test this hypothesis, we first validated our oxidative phosphorylation results by conducting a mitochondrial stress assay and observed YAP could increase oxidative phosphorylation. We then treated five sarcoma cell lines representing multiple subtypes with a complex 1 inhibitor to block oxidative phosphorylation, a YAP inhibitor, or both. From this, we noted a decrease in cell proliferation when treating with either drug and a synergistic effect when treating with both drugs. In addition, using CRISPR we knocked out endogenous YAP and assessed the transformation potential of PI3K in-vitro. We observed that PI3K tumors depend on YAP amplification for survival and proliferation.

Conclusion: Sarcoma heterogeneity is multilayered. Apart from patient and histological heterogeneity, intratumoral and intrasubtype heterogeneity is seen in subsets like UPS. Here we demonstrated the feasibility of targeting YAP and oxidative phosphorylation in multiple sarcoma subtypes. Using our osteosarcoma model, we observed amplification of YAP and showed these tumors depend on YAP for survival. These studies will lay the groundwork for early phase trials investigating YAP inhibition and support further mechanistic investigations focused on the role of YAP as a driver of sarcoma development and transformation.