Co-treatment with vactosertib, a novel, orally bioavailable activin receptor-like kinase 5 inhibitor, suppresses radiotherapy-induced epithelial-to-mesenchymal transition, cancer cell stemness, and lung metastasis of breast cancer

Abstract

Background: Acquired metastasis and invasion of cancer cells during radiotherapy are in part due to induction of epithelial-to-mesenchymal transition (EMT) and cancer stem cell (CSC) properties, which are mediated by TGF-β signaling. Here we evaluated the anti-metastatic therapeutic potential of vactosertib, an orally bioavailable TGF-β type I receptor (activin receptor-like kinase 5, ALK5) inhibitor, via suppression of radiation-induced EMT and CSC properties, oxidative stress generation, and breast to lung metastasis in a breast cancer mouse model and breast cancer cell lines. Materials and methods: Co-treatment of vactosertib with radiation was investigated in the 4T1-Luc allografted BALB/c syngeneic mouse model and in 4T1-Luc and MDA-MB-231 cells. The anti-metastatic therapeutic potential of vactosertib in breast cancer was investigated using fluorescence immunohistochemistry, real-time quantitative reverse transcription-polymerase chain reaction, western blotting, wound healing assay, mammosphere formation assay, and lung metastasis analysis in vitro and in vivo. Results: Radiation induced TGF-β signaling, EMT markers (Vimentin, Fibronectin, Snail, Slug, Twist, and N-cadherin), CSC properties (expression of pluripotent stem cell regulators, mammosphere forming ability), reactive oxygen species markers (NOX4, 4-HNE), and motility of breast cancer cells in vitro and in vivo. Vactosertib attenuated the radiation-induced EMT and CSC properties by inhibiting ROS stress in breast cancer. Moreover, vactosertib combined with radiation showed a significant anti-metastatic effect with suppression of breast to lung metastasis in vivo. Conclusions: These results indicate that inhibition of TGF-β signaling with vactosertib in breast cancer patients undergoing radiotherapy would be an attractive strategy for the prevention of cancer metastasis and recurrence. © 2022 Jiwon Choi, Jiyoung Park, Ilyoung Cho, Yhunyhong Sheen, published by Sciendo.