Abstract 4099: Targeting the paracaspase MALT1: A potential therapy to overcome ibrutinib resistance in relapsed/refractory MCL patients

Mantle cell lymphoma (MCL) is an aggressive B cell malignancy that is not yet curable. Ibrutinib was FDA-approved in 2013 to treat relapsed/refractory MCL; however, ibrutinib resistance inevitably develops. Once patients relapse after ibrutinib treatment, the 1-year survival rate is only 22%; therefore, there is an urgent unmet need to overcome ibrutinib resistance and to study alternative treatment options. Constitutive NF-κB activation is the hallmark of MCL. Indeed, next generation sequencing analysis of 110 MCL patient samples revealed that genes in the NF-κB signaling pathway had the highest mutation rates (28.8%), indicating the significant contribution of NF-κB signaling to MCL malignancy. Mucosa-associated lymphoid tissue transformation protein (MALT1) plays a crucial role in NF-κB signaling. MALT1 is a unique paracaspase within the human genome, and the proteolytic activity of MALT1 has been found to be constitutively active in many MCL samples, suggesting MALT1 may be a potential therapeutic target without significant off-target side effects. MI-2 is a specific inhibitor of MALT1 and its efficacy and safety are currently being evaluated in a clinical trial with ABC-type diffuse large B cell lymphoma patients. Mice treated with MI-2 did not have detectable physiological, histological or biochemical signs of toxicity. However, whether MALT1 activity contributes to ibrutinib resistance and whether targeting MALT1 can overcome ibrutinib resistance in relapsed/refractory MCL patients remain unclear. In this study, we found that both canonical and non-canonical NF-κB signaling is activated in ibrutinib-resistant MCL cells, which correlates with constitutive MALT1 activity. Interestingly, we found that MALT1 is highly mutated in four clusters, including the death domain, TRAF6-binding site, Caspase-like domain, and IKKγ-binding site in MCL samples. Occurrence of L79P, K80R, E319D, L445P and N446S was also highly correlated with ibrutinib resistance and disease progression, which requires more detailed investigation. Treatment with MI-2 significantly reduced cell viability in several MCL cell lines with nanomolar activity. MI-2 treatment inhibited NF-κB activation, IL-6 production and its downstream STAT3 activation. Combining MI-2 with ibrutinib resulted in synergistic growth inhibition in both ibrutinib-resistant MCL cell lines and primary MCL cells. These findings suggest that targeting MALT1 catalytic activity in MCL is a promising therapy to overcome ibrutinib resistance in relapsed/refractory MCL patients. The effect of MI-2 in in vivo PDX models is currently under investigation. This work and follow-up in vitro and in vivo studies will provide strong evidence that targeting MALT1 with MI-2 may be an effective novel therapeutic approach to overcome ibrutinib resistance. Citation Format: Changying Jiang, Shengjian Huang, Xin Lin, Michael Wang, Liang Zhang. Targeting the paracaspase MALT1: A potential therapy to overcome ibrutinib resistance in relapsed/refractory MCL patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4099. doi:10.1158/1538-7445.AM2017-4099