MCL-101: Using the Iron Chelator Deferasirox to Overcome Drug Resistance in Mantle Cell Lymphoma

Abstract

<h3>Context</h3> Mantle cell lymphoma (MCL) is a difficult-to-treat B-cell malignancy characterized by the t(11;14) translocation, resulting in cyclin D1 (CD1) overexpression. Despite advancements in MCL treatment, most patients still relapse. For instance, although the introduction of ibrutinib for relapsed/refractory MCL significantly improved the outcomes of MCL patients, ibrutinib resistance has become a clinical obstacle. MCL treatments are thus pursued by studying novel agents with a broad spectrum of targets or by rationally combining existing therapies aiming for synergistic anti-tumor activities. Deferasirox (DFX) is a clinically approved iron chelator with little to no side effects. We have previously shown that DFX exerts a vigorous anti-tumoral effect via growth inhibition and induction of apoptosis in MCL cells through ROS elevation, triggering of oxidative stress, induction of DNA damage, modulating PI3K/AKT/GSK3β signaling, and most importantly eliminating CD1 expression. The capacity of DFX to affect a multitude of targets establishes a solid basis for a possible synergistic interaction with other drugs, such that may overcome drug resistance in MCL. <h3>Objectives</h3> This study focuses on assessing the efficiency of DFX combined with the established therapeutic-agents etoposide, cytarabine, and ibrutinib in MCL cell-lines. <h3>Results</h3> We found that DFX synergizes with etoposide, cytarabine, and ibrutinib, prompting remarkable anti-tumoral effects in MCL cells with combination index (CI) values < 1. Interestingly, the DFX-drug combinations achieved synergism regardless of the innate sensitivity of the cell-lines to the treatment: ibrutinib-resistant cells restored their sensitivity to the drug when it was combined with DFX. In addition, we found that the sensitivity of MCL cells toward the drugs correlated with the drugs' ability to induce CD1 degradation. In agreement, DFX co-treatment enhanced CD1 degradation, especially in resistant cells. <h3>Conclusion</h3> We show here that DFX is a putative promising drug-sensitizing agent for the treatment of MCL. DFX-co-treatment not only enhances the efficacy of the tested drugs but also restores the anti-proliferative activity of the drugs in resistant MCL cells. To the best of our knowledge, this study is the first to provide evidence on the potential of DFX to overcome drug resistance in MCL.