Overcoming ibrutinib resistance in mantle cell lymphoma

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Project Abstract Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK) and similar inhibitors of B-cell receptor (BCR)- associated kinases are shifting the therapeutic landscape in B-cell neoplasia. However, the development of resistance in patients treated with these agents is associated with rapidly progressive disease and death. Mutations in BTK and its downstream target phospholipase Cγ2 have been implicated in resistance to ibrutinib in chronic lymphocytic leukemia (CLL). While such mutations are found in a subset of mantle cell lymphoma (MCL) patients, they do not account for all patterns of ibrutinib resistance. Recent studies have implicated nuclear factor-κB (NFκB) as a potential critical component of resistance in MCL. The pathogenic contribution of NFκB is supported by identification of a) activation of NFκB signaling pathways within the lymph node microenvironment; b) constitutive NFκB activity resulting from recurrent mutations in TRAF2, BIRC3 and RELA; and c) mutations in genes affecting NFκB signaling in primary ibrutinib-refractory MCL samples. Thus, tumor-intrinsic and microenvironment-driven NFκB activation may underlie a significant fraction of ibrutinib failures. However, the role of NFκB has not been studied prospectively in this setting. We hypothesize that NFκB and its transcriptional targets are upregulated in patients who exhibit resistance to ibrutinib. Under Aim 1, we will conduct a prospective study to determine functional significance of NFκB activation in ibrutinib resistance in MCL. We will comprehensively evaluate NFκB signaling in primary MCL cells obtained from bone marrow and/or lymph nodes prior to the start of ibrutinib, on therapy and at relapse. Given the emerging importance of NFκB in MCL, an optimal therapeutic approach would incorporate targeting NFκB activation. In evaluating the NFκB pathway as a therapeutic target, we discovered that it can be neutralized via blockade of upstream regulators in the ubiquitin-proteasome system (UPS). Our data indicate that NFκB activity may be blocked by targeting NEDD8-activating enzyme (NAE; a ubiquitin-like modifier) in neoplastic B-cells, resulting in cell apoptosis. We hypothesize that therapeutic disruption of NFκB by blocking the NAE will overcome ibrutinib resistance in MCL. Thus, Aim 2 will evaluate therapeutic targeting of the E1 ligase, NAE, in ibrutinib- resistant MCL. We will elucidate functional effects of inhibiting NAE on NFκB signaling, cell apoptosis in MCL cell lines and primary ibrutinib-resistant cells in vitro and in a murine MCL xenograft model. Finally, Aim 3 will assess the NAE inhibition-mediated deregulation of NFκB in neoplastic B cells and T cells obtained from patients who receive treatment with pevonedistat and ibrutinib on a clinical trial. Our study will test novel approaches to overcome ibrutinib resistance through NFκB inactivation, and thus significantly impact MCL therapeutics.