HER2 IN SOFT TISSUE SARCOMAS: A NOVEL POTENTIAL THERAPEUTIC TARGET

Background: Soft tissue sarcomas (STS) are rare and biologically heterogeneous malignancies with limited systemic treatment options in the advanced setting. While HER2 is an established therapeutic target in several epithelial cancers, its role in sarcomas remains poorly defined. The development of next-generation antibody–drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd), has renewed interest in HER2 as a potential therapeutic vulnerability even in tumors with low or heterogeneous expression. Methods: A panel of human sarcoma cell lines representing multiple histologies (leiomyosarcoma, liposarcoma, gastrointestinal stromal tumor, epithelioid sarcoma, and chordoma) was analyzed. HER2 surface expression was quantified by flow cytometry using HER2-high and HER2-low breast cancer cell lines as controls. Antitumor activity of T-DXd was assessed through 72-hour cell viability assays, and IC50 values were calculated from dose–response curves. Exploratory correlations between HER2 expression and drug sensitivity were evaluated. Results: Detectable HER2 surface expression was observed in all tested sarcoma models, although generally at low-to-moderate levels compared with HER2-amplified breast cancer controls. Considerable inter-model heterogeneity emerged. Among conventional STS models, myxoid liposarcoma demonstrated the greatest sensitivity to T-DXd (IC50 29.37 µg/mL), which was maintained in a trabectedin-resistant derivative (IC50 26.71 µg/mL). Notably, one chordoma model (CH22) showed marked sensitivity (IC50 4.73 µg/mL), exceeding that of the HER2-low MCF7 breast cancer comparator (IC50 92.11 µg/mL). Epithelioid sarcoma models displayed variable responses, while leiomyosarcoma, dedifferentiated liposarcoma, and GIST models were less responsive. HER2 expression levels alone did not fully predict T-DXd sensitivity, suggesting additional biological determinants of response. Conclusions: HER2 is consistently detectable across several sarcoma models and may function as a therapeutically exploitable surface antigen rather than a classical oncogenic driver. Selected sarcoma subtypes, particularly myxoid liposarcoma, chordoma, and some epithelioid sarcomas, demonstrated meaningful preclinical sensitivity to T-DXd despite low HER2 expression. These findings support further translational and clinical investigation of HER2-directed ADC strategies in molecularly selected sarcoma populations.