Combination of Lenvatinib and Antibiotics: A Potential Approach to Enhance Sensitivity in Differentiated Thyroid Cancer.

Abstract

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 limit its use. A novel approach to sensitize tumor cells to therapy is the administration of antibiotics that target mitochondrial metabolism. We analyzed the effects of a combination of lenvatinib with the tetracycline-class antibiotics tigecycline and eravacycline in DTC cells with reduced response to lenvatinib and explored the underlying mechanism of action. Cell viability was quantified after treatment with either single agents or combination therapies consisting of lenvatinib with tigecycline or eravacycline. Baseline oxidative metabolism and drug-induced changes in oxygen consumption rate were measured. 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. We found that combining lenvatinib with tigecycline or eravacycline resulted in stronger reductions in 2D and 3D cell viability compared to single-agent treatments in K1 DTC cells, which show limited lenvatinib responsiveness. 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. Although limited to in vitro models and subject to pharmacological limitations, our findings provide a mechanistic proof-of-concept that mitochondria-targeting antibiotics may enhance lenvatinib responsiveness in a DTC cell line.