Objective: Uterine carcinosarcoma (UCS) is a rare but highly aggressive malignancy with biphasic growth pattern. This morphology can be attributed to epithelial-mesenchymal transition (EMT) that often associates with tumor invasion and metastasis. Accordingly, we analyzed a novel patient-derived preclinical model to explore whether EMT is a potential target in UCS. Methods: A novel UCS cell line (PF338) was established from the malignant pleural effusion of a 59-year-old patient at time of disease progression. Immunohistochemistry was performed in primary and metastatic tumor lesions. Oncogenic mutations were identified by next-generation sequencing. Viability assays and cell cycle analyses were used to test in vitro sensitivity to different standard and novel treatments. E-cadherin, β-catenin and pSMAD2 expressions were measured by immunoblot. Results: Whereas immunohistochemistry of the metastatic tumor showed a predominantly sarcomatous vimentin positive tumor that has lost E-cadherin expression, PF338 cells demonstrated biphasic growth and carried mutations in KRAS, PIK3CA, PTEN and ARID1A. PF338 tumor cells were resistant to MEK- and TGF-β signaling-inhibition but sensitive to PIK3CA- and PARP-inhibition and first-line chemotherapeutics. Strikingly, histone deacetylase (HDAC) inhibition markedly reduced cell viability by inducing a dose-dependent G0/1 arrest and led to mesenchymal-epithelial transition as evidenced by morphological change and increased E-cadherin and β-catenin expression. Conclusions: Our data suggest that HDAC inhibition is effective in a novel UCS cell line by interfering with both viability and differentiation. These findings emphasize the dynamic manner of EMT/MET and epigenetics and the importance of molecular profiling to pave the way for novel therapies in UCS.