Combination of Lenvatinib and Antibiotics: A Potential Approach to Overcome Resistance in Differentiated Thyroid Cancer

Background/Objectives: Approved in 2015 for radioiodine-refractory differentiated thyroid carcinoma (RR-DTC), the multikinase inhibitor lenvatinib has demonstrated substantial efficacy; nevertheless, severe adverse effects, intrinsic resistance or development of acquired resistance often limits its use. A novel approach to potentially overcome therapy resistance of tumors is the administration of antibiotics that target mitochondrial metabolism. We therefore combined lenvatinib with the tetracycline-class antibiotics tigecycline and eravacycline in lenvatinib-resistant DTC cells and explored the underlying mechanism of action. Methods: Cell viability was quantified after treatment with either single agents or combination therapies consisting of lenvatinib with tigecycline or lenvatinib with eravacycline. Baseline oxidative metabolism and drug-induced changes in oxygen consumption rate were measured using the Seahorse XFe96 Analyzer. Three-dimensional spheroid cultures were used to better mimic the in vivo tumor milieu. Apoptosis was assessed by caspase-3/7 activity, and expression of apoptosis-related proteins was elucidated by immunoblotting. Results: Combining lenvatinib with tigecycline or eravacycline synergistically reduced the 2D and 3D cell viability of lenvatinib-resistant DTC cells. Both combination therapies markedly impaired mitochondrial respiration, accompanied by down-regulation of anti-apoptotic Bcl-2 family members, activation of caspase-3/7, and cleavage of Poly (ADP-ribose) polymerase (PARP), which are hallmarks of apoptosis. Conclusion: Our study provides evidence of the combination of lenvatinib with mitochondria-targeting antibiotics as a promising strategy to overcome resistance in DTC by impairing mitochondrial function and promoting apoptotic cell death.