Single-Agent Bruton's Tyrosine Kinase (Btk) Inhibitor and Single-Agent Carfilzomib Induce Cell Apoptosis, Arrest Cell Growth and Downregulate NF-Kb Activity In Mantle Cell Lymphoma

Abstract 4971

Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma with poor prognoses. Discovery of less-toxic and better therapeutic agents is an ongoing challenge. Bruton tyrosine kinase (BTK), is identified as an essential kinase for B-cell survival, activated through the B-cell receptor (BCR) pathway. Recent studies have indicated that BTK mediates NF-kB activation. The potential therapeutic agent PCI-32765, a novel BTK inhibitor (Pharmacyclics, Sunnyvale, CA) have shown effective preliminary targeting of these pathways in MCL. Carfilzomib, a 2^nd generation proteasome inhibitor (Onyx Pharm. Inc., Emeryville, CA) proven effective in myeloma in clinical trial is also effective in MCL in vitro and in vivo in pre-clinical studies. The objective of our study was to evaluate the therapeutic efficacy of PCI-32765 and carfilzomib in MCL, and elucidate the mechanisms of their actions. We initially screened 12 MCL cell lines and discovered that Btk is constitutively phosphorylated in all MCL cells. Representative MCL cell lines, both classic and blastoid variant, were utilized for in vitro studies. PCI-32765 effectively inhibited phospho-BTK, leading to reduced MCL cell growth with IC:50 values range from 10–50 uM. PCI-32765 also induced MCL cell apoptosis in both dose- and time-dependent manner as well as carfilzomib. Using luciferase pGL3 reporter plasmid (6xNF-kB-CD40L/TKm), we demonstrated that both PCI-32765 and carfilzomib down-regulated the reporter with a dosage dependent manner. Our data suggest that strategic targeting of growth/survival pathways with novel therapeutic agents PCI-32765 and carfilzomib should provide a novel therapy regimen for patients with relapsed/refractory MCL.