Targeting The Tgf Beta Pathway In Uterine Carcinosarcoma

Uterine carcinosarcoma (UCS) is a relatively infrequent, but extremely aggressive endometrial malignancy. Although surgery and chemotherapy have improved outcomes, overall survival (OS) remains dismal due to the lack of targeted therapy and biphasic (epithelial and mesenchymal) nature that renders the tumor aggressive and difficult to manage. Here we report a role of transforming growth factor-beta (TGF beta) in maintaining epithelial to mesenchymal transition (EMT) phenotype and aggressiveness in UCS. Using a 3D-culture system, we evaluated the efficacy of the transforming growth factor-beta receptor-I (TGF beta-R1) kinase inhibitor Galunisertib (GLT), alone and in combination with standard chemotherapeutic drugs used for the management of UCS. We demonstrate that GLT by inhibiting canonical and non-canonical signaling emanating from transforming growth factor-beta 1 (TGF beta 1) reduces cellular viability, invasion, clonal growth and differentiation. Interestingly, GLT sensitizes UCS cells to chemotherapy both in vitro and in in vivo preclinical tumor model. Hence, targeting TGF beta signaling, in combination with standard chemotherapy, may be exploited as an important strategy to manage the clinically challenging UCS.