Effects of TGF-β Inhibitor on Chemoresistance in Ovarian Cancer Models

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Authors
Bishop, Rachel N.
Keyword
TGF-Beta , Ovarian Cancer , Chemotherapy , Chemoresistance , Galunisertib/LY
Abstract
High grade serous ovarian carcinoma (HGSC) is the most fatal gynecological cancer, due to the aggressive, heterogeneous nature of the tumours. Despite an initially favourable treatment response, patients with HGSC often develop resistance to the first-line platinum-based chemotherapies. In addition, the few currently available second line treatments, such as doxorubicin (Dox), often fail to elicit a significant response in platinum resistant HGSC. High levels of Transforming Growth Factor-β (TGF-β) was linked to poor prognosis, chemoresistance and metastasis risk in HGSC. Mechanisms include roles of TGF-β promoting epithelial to mesenchymal transition (EMT) and immune evasion via suppression of Granzyme B (Gzmb) and Perforin (Prf1) expression in cytotoxic T cells. We hypothesized that treatments of HGSC models with TGFβR1 inhibitor galunisertib (LY) would increase sensitivity to chemotherapy drugs such as doxorubicin (Dox). Using several human and mouse HGSC cell models treated with LY, we observed reversal of EMT and increased Dox sensitivity. We extended these studies to a syngeneic mouse HGSC model comparing treatments with vehicle, Dox, LY, or the Dox/LY combination. Compared to vehicle control, all treatments significantly decreased the tumour burden with the combination having the smallest tumours. Unfortunately, the Dox dose was not optimal to test for synergy with LY treatments. However, in HGSC tumours from LY-treated mice we detected reduced expression of mesenchymal genes SNAIL and CDH2, while increasing expression cytotoxicity-related genes Gzmb and Prf1 compared to vehicle control. These differences in gene expression were highly significant in mice classified as LY responders versus non-responders. Together, these results provide rationale for further testing of TGF-β inhibitors in combination with chemotherapy and/or immunotherapy to limit HGSC recurrence and progression.
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