Abstract

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and lethal malignancies, with limited treatment options and poor clinical outcomes. KU-57788, a selective inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), has shown promise in cancer therapy when combined with radiotherapy and chemotherapy. However, its therapeutic potential and underlying mechanisms in ATC remain unclear. In this study, we demonstrate that KU-57788 exerts potent anti-ATC activity both in vitro and in vivo by inducing DNA damage and triggering mitotic catastrophe. Unexpectedly, we identify a novel mechanism whereby KU-57788 directly binds to and activates dynamin-related protein 1 (DRP1), leading to excessive mitochondrial fission and fragmentation. This process is accompanied by the protective activation of the NRF2/SLC7A11/GSH axis, which mitigates the cytotoxic effects of KU-57788. Notably, pharmacological induction of ferroptosis or cystine depletion effectively synergizes with ATC cells to KU-57788, overcoming resistance and promoting ferroptosis. Collectively, our findings highlight the therapeutic potential of KU-57788 in ATC while revealing an intrinsic resistance mechanism mediated by DRP1 activation and the potential involvement of the NRF2/SLC7A11/GSH axis. More importantly, we provide strong evidence that combining KU-57788 with ferroptosis inducers significantly enhances its anticancer efficacy, offering a promising therapeutic strategy for ATC. The alternative text for this image may have been generated using AI.