Abstract 4563: Mechanism of action of Ibrutinib in mantle cell lymphoma

Abstract

Abstract Mantle cell lymphoma (MCL), accounting for about 5-6% of non-Hodgkin lymphoma (NHL), is one of the lymphomas with very poor prognosis (median survival 3-5years).Ibrutinib, a newly approved Bruton's tyrosine kinase (BTK) inhibitor, showed remarkable clinical benefits in MCL. However, the mechanism underlining the clinical activity is not well understood. In this study, we identified MCL cell lines that were sensitive and resistant to ibrutinib. We showed that ibrutinib induced G1 cell cycle arrest in sensitive cell lines at 3-day treatment and eventually led to cell death after prolonged compound incubation. Physiologically relevant low concentration of ibrutinib inhibited phosphorylation of IKB(S32), p65/RelA(S536) and nuclear translocation of NF-κB components. Inhibition of NF-κB signaling decreased IRF4 and c-Myc level, which was accompanied with decrease of CDK6 and phosphor-RB (S807/811) level, meanwhile elevated p27/Kip1. Activation of NF-κB pathway with PKC agonist rescued ibrutinib induced G1 cell cycle arrest and eventually attenuated the cell killing effect. IRF4 phospho-RB and CDK6 level were also rescued by PKC agonist. BTK/PKC/NF-κB pathway and PI3K/AKT/mTOR pathway showed compensatory effect in MCL cell lines. Activating NF-κB pathway with PKC agonist compensated the cell killing effects of idelalisib or everolimus. Additionally, we showed that ibrutinib synergized with idelalisib or everolimus on cell killing of MCL cell lines, suggesting combination therapeutic strategies for MCL. Citation Format: Zhijian Sun, Dongping Zhou, Min Wei, Lusong Luo. Mechanism of action of Ibrutinib in mantle cell lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4563. doi:10.1158/1538-7445.AM2014-4563