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

## TL;DR

Undifferentiated pleomorphic sarcoma is a genetically diverse cancer, making it hard to treat with targeted therapies, though immune checkpoint inhibitors show some promise.

## Contribution

The paper reviews the genetic complexity of UPS and evaluates the potential for targeted therapies based on recent findings.

## Key findings

- UPS exhibits extensive genetic heterogeneity, including mutations, amplifications, and chromosomal translocations.
- Immune checkpoint inhibitors are currently the only validated targeted therapy for UPS.
- Molecular profiling alone offers limited guidance for treatment, suggesting the need for ex vivo and in vitro testing.

## Abstract

Despite advances in multitargeted anticancer drugs and personalized treatment approaches, the management of soft tissue sarcoma remains challenging. Among the most difficult subtypes to diagnose and treat with targeted therapies is UPS, owing to its high degree of genetic heterogeneity. This review summarizes recent findings on the genetics and epigenetics of this sarcoma subtype and discusses the potential application of various targeted therapies.

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.