Targeting the TGFβ pathway in uterine carcinosarcoma

Authors:

Shailendra Kumar Dhar Dwivedi1, Geeta Rao2, Anindya Dey1, Megan Buechel1, Yushan Zhang2, Min Zhang3, Da Yang3, Priyabrata Mukherjee2, Resham Bhattacharya1,4
PDF Download PubMed Link
Affiliations:

1 Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

2 Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

3 Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.

4 Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Keywords: 

Uterine carcinosarcoma, Galunisertib, TGFβ1.

Abbreviations:

CT – carboplatin/ paclitaxel treatment;

ECM – extracellular matrix;

EMT – epithelial to mesenchymal transition;

GLT – Galunisertib;

TGF – transforming growth factor;

TDT – tumor doubling time;

UCS – uterine carcinosarcoma.

Corresponding Author(s):

Resham Bhattacharya Ph.D., Associate Professor, Department of Obstetrics and Gynecology, Peggy and Charles Stephenson Cancer Center, OUHSC, 975 NE 10th Street, BRC-1409B, Oklahoma City, OK 73104; Resham-Bhattacharya@ouhsc.edu

Conflict of interest statement:

None to declare.

Please cite this article as:

Shailendra Kumar Dhar Dwivedi, Geeta Rao, Anindya Dey, Megan Buechel, Yushan Zhang, Min Zhang, Da Yang, Priyabrata Mukher-jee, Resham Bhattacharya (2020). Targeting the TGFβ pathway in uterine carcinosarcoma. Cell Stress 4(11): 252-260. doi: 10.15698/cst2020.11.234

© 2020 Dwivedi et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.

Abstract:

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-β (TGFβ) 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-β receptor-I (TGFβR1) 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-β1 (TGFβ1) 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 TGFβ signaling, in combination with standard chemotherapy, may be exploited as an important strategy to manage the clinically challenging UCS.