Shh Pathway Inhibitor LDE225 (Sonidegib) Limits BCRP Activity and Decreases Topotecan Resistance in Monolayer and Spheroid Models of Ovarian Cancer

Resistance to topotecan (TOP) limits effectiveness of chemotherapy in recurrent ovarian cancer. Increased activity of ATP-binding cassette (ABC) transporters, including breast cancer resistance protein (BCRP), is one of the mechanisms implicated in the development of TOP resistance. LDE225 (Sonidegib), a Smoothened (SMO) inhibitor targeting the Sonic Hedgehog pathway, has demonstrated antitumor properties, but its activity in TOP-resistant ovarian cancer remains insufficiently characterized. Here, we investigated LDE225 in A2780 ovarian cancer cells and their TOP-resistant, BCRP-overexpressing sublines using two-dimensional (2D) and three-dimensional (3D) models, which are relevant settings for investigating BCRP-associated TOP resistance in ovarian cancer. LDE225 reduced cell proliferation, colony formation, and migration in both TOP-sensitive and TOP-resistant cells. It also exhibited TOP-independent cytotoxicity and restored TOP sensitivity in resistant cells in both culture models. Although LDE225 did not reduce BCRP expression, fluorescence microscopy and flow cytometry demonstrated decreased transporter activity following treatment. Collectively, these findings demonstrate that LDE225 affects several phenotypic features of ovarian cancer cells and may be associated with the restoration of TOP sensitivity in resistant cells. Reduced BCRP activity may contribute to this effect, although the underlying mechanism requires further investigation. These findings support further evaluation of LDE225 as a single agent or in combination with TOP in TOP-resistant ovarian cancer.