Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by an initial high response to first line treatment, followed by a continuous relapse, resulting in a discouraging long term outcome. Recently a novel potent inhibitor of BTK, ibrutinib, was found to induce impressive response in B-cell malignancies and has been approved for therapy of refractory mantle cell lymphoma. BTK (bruton's tyrosine kinase) is required for B cell receptor signaling (BCR) and is essential for B cell development, differentiation, signaling and survival. Despite its unprecedented clinical activity, acquired resistance to ibrutinib also develops, pushing the evaluation of new drug combinations. We have recently shown that Chk1 inhibitors (PF-00477736) not only are very effective as single agents in MCL but are strongly synergistic with Wee1 inhibitors. We tested ibrutinib in combination with PF-00477736 in different MCL cell lines (JVM2, JEKO-1, MAVER-1, GRANTA-519, REC1), finding that the combination is synergistic in all these cell lines, with Combination Index values, evaluated at the IC50 doses, ranging from 0.5 to 0.7. The combination was also very active in a JEKO-1 cell line made resistant to PF-00477736. The synergistic effect of the combination was also observed using another Chk1 inhibitor (AZD-7762). Western Blot Analysis revealed that the combined treatment at concentrations of ibrutinib and PF-00477736 not toxic as single agents, neutralized the increase in phosphor-ERK observed after PF-00477736 treatment, and led to a substantial decrease in the active phosphorylated form of BTK in Y223. Cell cycle analysis and apoptosis are undergoing to try to dissect the cytotoxic mechanisms induced by the combination along with studies aiming at elucidating the molecular mechanisms at the basis of this combination. These data would suggest that ibrutinib in combination with Chk1 inhibitors could be a new and effective therapeutic strategy to test in clinical setting in MCL.
Citation Format: Valentina Restelli, Micaela Vagni, Monica Lupi, Francesco Bertoni, Giovanna Damia, Laura Carrassa. Combining ibrutinib with Chk1 inhibitors as a new therapeutic strategy for mantle cell lymphoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C193.