Abstract
Abstract Constitutive activation of B-cell receptor (BCR) signaling is a major driving mechanism for the proliferation and survival of various B-cell lineage non-Hodgkin lymphomas (NHL). Blocking BCR signaling using the first-in-class Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, has proved effective and is currently FDA approved for the treatment of several B-cell lymphomas. Unfortunately, significant subsets of patients possess either primary or acquired resistance to ibrutinib, often resulting in worse prognosis and poorer responses to subsequent therapies. Therefore, overcoming ibrutinib resistance is an urgent clinical need requiring new tools to both delineate the molecular mechanisms of resistance and develop viable therapeutics. To that end, we developed a mantle cell lymphoma (MCL) cell line, MCIR1, from a patient with clinically acquired ibrutinib resistance. MCIR1 is a bona fide MCL cell line featuring CD19+/CD5+/CD10-/CD23-/t(11;14)+/TP53+/-; and lacking the previously described mutations in BTK (C481S) and phospholipase C-gamma-2 (R665W, L845F). Importantly, MCIR1 cells possess hallmarks of ibrutinib resistance, including the insensitivity of ERK1/2 phosphorylation to ibrutinib in vitro, and the irresponsiveness of MCIR1 xenograft tumors to ibrutinib treatment in mice as compared with ibrutinib-sensitive Jeko-1 tumors. To delineate the molecular mechanism(s) of ibrutinib resistance, we identified by RNA-Seq analysis that MCIR1 cells possess robust activity of the non-canonical NFkB pathway and elevated expression of NFkB target genes, suggesting that this pathway likely drives their resistance to ibrutinib. Finally, we demonstrated the utility of MCIR1 as a tool for testing new drugs to combat ibrutinib resistance in vitro by showing its sensitivity to the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein inhibitor, venetoclax. To our knowledge, MCIR1 is the first patient-derived ibrutinib-resistant cell line to be established. Hence, MCIR1 is especially useful because uniquely possesses the relevant clinical and biological features of patients with ibrutinib-resistant MCL. We propose MCIR1 as a tool to further the understanding of molecular mechanisms conferring ibrutinib resistance by providing a clinically relevant system with the capacity for molecular and genetic manipulations. Further, these features make MCIR1 an ideal model to screen drugs for combating ibrutinib resistance through both in vivo and in vitro approaches. Citation Format: Kevin E. Nowakowski, Jithma P. Abeykoon, Mary J. Stenson, Michael M. Timm, Curtis A. Hanson, Daniel L. Van Dyke, Anne J. Novak, Xiaosheng Wu, Thomas E. Witzig. MCIR1: A patient-derived ibrutinib-resistant mantle cell lymphoma line for the study of ibrutinib resistance and drug discovery [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 650.
Published Version
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