Genetic Heterogeneity of Undifferentiated Pleomorphic Sarcoma: Is There Potential for Targeted Therapy?

Undifferentiated pleomorphic sarcoma (UPS) is the most morphologically and genetically heterogeneous form of soft tissue sarcoma. UPS tumors can exhibit a wide range of genetic abnormalities, including activating and inactivating mutations, gene amplifications, chromosomal translocations, and copy number variations. Owing to this extensive genetic heterogeneity, no UPS-specific therapeutic targets have yet been validated, complicating diagnosis, prognosis, and the selection of targeted treatment strategies. Currently, immune checkpoint inhibitors (targeting PD-1, PD-L1, and CTLA-4) are the only validated targeted therapy for UPS, reflecting the frequent mutational events that activate immune response pathways. Because molecular genetic profiling alone provides limited prognostic value for chemoresistance in UPS, the development of experimental ex vivo and in vitro testing approaches may help to identify and exclude potentially ineffective targeted therapies. © 2025 by the authors.