Using the iron chelator deferasirox to overcome drug resistance in mantle cell lymphoma
2Hematology Division, Davidoff Cancer Center, Rabin Medical Center, Israel
3Sackler School of Medicine, Tel Aviv University, Israel
Mantle cell lymphoma (MCL) is a difficult-to-treat B-cell malignancy characterized by cyclin D1 (CD1) overexpression and deregulation of pathways such as B-cell receptor, PI3K/AKT/GSK3β and NFκB. Despite advancements in MCL treatment, such as the introduction of ibrutinib, resistance has become a formidable obstacle and most patients will eventually relapse. MCL treatments are thus pursued by studying novel agents with a broad spectrum of targets or by rationally combining therapies aiming for synergistic activities. Deferasirox (DFX) is a clinically approved iron chelator. We have previously shown that DFX exerts an 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 eliminating CD1 expression. The capacity of DFX to affect numerous targets establishes the basis for a possible synergistic interaction with other drugs that may overcome drug resistance in MCL.
We found that DFX synergizes with etoposide, cytarabine and ibrutinib, prompting anti-tumoral effects in MCL cells with combination index (CI)<1. The DFX-drug combinations achieved synergism regardless of the innate sensitivity of the cell-lines to the treatment: ibrutinib-resistant cells restored sensitivity to the drug when it was combined with DFX. Additionally, we found that the MCL cells` sensitivity towards the drugs correlated with the drugs ability to induce CD1 degradation. In agreement, DFX co-treatment enhanced CD1 degradation, especially in resistant cells.
To the best of our knowledge, this study is the first to provide evidence on the potential of DFX to overcome ibrutinib resistance in MCL.