Lomitapide enhances cytotoxic effects of temozolomide in chemotherapy-resistant glioblastoma.

Abstract

More than a third of patients with glioblastoma experience tumor progression during adjuvant therapy. In this study, we performed a high-throughput drug repurposing screen of FDA-approved agents capable of crossing the blood-brain barrier in order to find agents to counteract acquired or inherent glioma cell resistance to temozolomide-associated cytotoxicity. We identified the cholesterol processing inhibitor, lomitapide, as a potential chemosensitizer in glioblastoma. In vitro treatment of temozolomide-resistant glioblastoma cells with lomitapide resulted in decreased intracellular ubiquinone levels and sensitized cells to temozolomide-induced ferroptosis. Concomitant treatment with lomitapide and temozolomide (TMZ) prolonged survival and delayed tumor recurrence in a mouse glioblastoma model, compared with treatment xwith TMZ alone. Our data identified lomitapide as a potential adjunct for treatment of temozolomide-resistant glioblastoma.