(P 58) PLK1 AS A VULNERABLE TARGET OF BAP1-DRIVEN UNDIFFERENTIATED PLEOMORPHIC SARCOMAS

Objective: Undifferentiated pleomorphic sarcoma (UPS) is one of the most common soft tissue sarcomas (STS) in adults, yet it remains lethal and understudied diseases. Additionally, UPS is genetically heterogenous and lacks recurrent oncogenic driver mutations, complicating efforts to develop broadly effective therapies. Consequently, a promising approach is to develop targeted therapies for UPS driven by specific tumor suppressor drivers. However, the molecular pathogenesis of UPS remains largely unknown, hindering the development of such therapies. Approximately 65% of UPS harbor TP53 mutations, but somatic mutation of Trp53 alone is insufficient to induce sarcomas in vivo. The role of other genes in facilitating Trp53-driven UPS is unknown. For instance, BAP1 deletion is dominantly associated with UPS among all STS. However, the role of BAP1 in UPS development is unexplored.

Methods: A tailored in vivo CRISPR/Cas9 screen of 35 tumor suppressor genes (TSG) commonly mutated in UPS, followed by individual gene validation in vivo, were conducted to identify TSG critical for UPS development. Additionally, total RNA sequencing, multiplex immunohistochemistry, flow cytometry, and preclinical trials using autochthonous mouse models of Bap1-driven UPS were utilized in the study.

Results: We discovered that Bap1 knockout cooperates with Trp53 knockout to induce metastatic UPS in vivo. We found that Bap1-driven UPS is poorly immunogenic, even at early stages. Additionally, a B cell signature may play a role in immune suppression caused by loss of Bap1. Moreover, we demonstrated that Polo-like Kinase 1 (Plk1) is critical for Bap1-driven sarcomagenesis. Finally, we demonstrated that a Plk1 inhibitor, volasertib, drastically inhibited tumor growth in an autochthonous mouse model of Bap1-driven UPS.

Conclusion: We determined that Bap1 is a potent tumor suppressor of UPS. Our findings pave the way for translating volasertib as a targeted therapy to treat patients with Bap1-driven UPS, a group currently lacking treatment option.