Sinonasal teratocarcinosarcoma (TCS) is a rare and highly aggressive tumor characterized by a diverse histology that includes epithelial, mesenchymal, neuroendocrine, and germ cell elements. Given its poor prognosis, there is an urgent need to develop new treatment strategies for TCS patients. Recent studies have identified recurrent mutations in SMARCA4 as potential therapeutic targets, with interest in using EZH1/2 and CDK4/6 inhibitors to counteract these genetic alterations.

In this study, we established the first in vitro cell line, TCS627, derived from a previously untreated primary TCS that originated in the ethmoid sinus and exhibited invasion into the brain. The TCS627 cells expressed a range of immunohistochemical markers, confirming their differentiation into epithelial, neuroepithelial, sarcomatous, and teratomatous components. Whole-exome sequencing of the cell line revealed 99 somatic mutations, including alterations in SMARCA4, ARID2, TET2, CDKN2A, WNT7A, NOTCH3, and STAG2, all of which were also detected in the primary tumor.

Focusing on the mutated SMARCA4 as a therapeutic target, growth inhibition assays demonstrated that TCS627 cells were highly responsive to the CDK4/6 inhibitor palbociclib, whereas the response to the EZH1/2 inhibitor valemetostat was considerably weaker. These findings suggest that targeting the SMARCA4 pathway, particularly through CDK4/6 inhibition, could represent a promising strategy for treating TCS.

In conclusion, the TCS627 cell line retains both the histologic and genetic hallmarks of TCS, making it a valuable model for basic research and preclinical evaluation of novel therapeutic options for patients suffering from this challenging malignancy. Lirametostat