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 C?2 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-?B (NF?B) as a potential critical component of resistance in MCL. The pathogenic contribution of NF?B is supported by identification of a) activation of NF?B signaling pathways within the lymph node microenvironment; b) constitutive NF?B activity resulting from recurrent mutations in TRAF2, BIRC3 and RELA; and c) mutations in genes affecting NF?B signaling in primary ibrutinib-refractory MCL samples. Thus, tumor-intrinsic and microenvironment-driven NF?B activation may underlie a significant fraction of ibrutinib failures. However, the role of NF?B has not been studied prospectively in this setting. We hypothesize that NF?B 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 NF?B activation in ibrutinib resistance in MCL. We will comprehensively evaluate NF?B 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 NF?B in MCL, an optimal therapeutic approach would incorporate targeting NF?B activation. In evaluating the NF?B 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 NF?B 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 NF?B 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 NF?B 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 NF?B 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 NF?B inactivation, and thus significantly impact MCL therapeutics.
Mantle cell lymphoma (MCL) is an incurable disease which manifests resistance to both conventional chemotherapy approaches and ibrutinib, a B cell receptor signaling inhibitor. Here we will use primary patient material to prospectively investigate the role of NF?B pathway activation in ibrutinib resistance in MCL. Armed with our preliminary data, we will evaluate a novel strategy to overcome this resistance by targeting the Nedd8- activating enzyme (NAE), by conducting investigations in vitro, in mouse models using ibrutinib-resistant MCL cell lines and patient-derived xenografts, and in a clinical trial of pevonedistat, an investigational inhibitor of NAE.
