Bortezomib enhances the anti-cancer effect of the novel Bruton's tyrosine kinase inhibitor (BGB-3111) in mantle cell lymphoma expressing BTK.

Xianhuo Wang,Bin Meng,Xiubao Ren,Tingting Zhang,Zhengzi Qian,Wei Li,Xianming Liu,Yue Fei,Lanfang Li,Lihua Qiu,Qiongli Zhai,Xiaohui Jia,Xia Liu,Shiyong Zhou,Huilai Zhang

doi:10.18632/aging.203314

Abstract

BGB-3111, a novel Bruton’s tyrosine kinase (BTK) inhibitor, shows promising anti-cancer effects in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), and Waldenstrom macroglobulinemia (WM). This study aimed to investigate the anti-cancer effects of BGB-3111 combined with bortezomib (BTZ) against the BTK-expressing MCL. We found that BTK, which was overexpressed in 59.4% of patients with MCL, was mainly characterized by high Ki67 and elevated MIPI scores. BGB-3111 strongly inhibited cell proliferation, induced cell cycle arrest in the G1/G0-phase, and promoted cell apoptosis in the MCL cells expressing BTK. BGB-3111 provides better safety than another BTK inhibitor, ibrutinib as ibrutinib inhibits the inducible T-cell kinase (ITK) as an off-target effect but BGB-3111 does not inhibit ITK. Low doses of BTZ enhanced the anti-cancer effect induced by the low dose of BGB-3111 by downregulating the expression levels of PARP and Bcl-2 and increasing the expression levels of cleaved PARP and cleaved caspase-9. In addition, low doses of BGB-3111, but not of BTZ, inhibited BTK phosphorylation. However, low-doses of BTZ strengthened the anti-cancer effect induced by the low-doses of BGB-3111 via synergistically suppressing the IκBα and P65 phosphorylation. Taken together, our findings validate that BGB-3111 is a novel and effective BTK inhibitor for MCL-expressing BTK. Hence, it can be harnessed as a potential therapeutic strategy through a combinatorial treatment comprising low-dose BGB-3111 and low-dose BTZ to gain strong anti-cancer effects and better safety for MCL patients.

Highlights

Mantle cell lymphoma (MCL) originates from B lymphocytes in the region of the small lymph node, which accounts for 3% to 10% of non-Hodgkin’s lymphoma (NHL) [1,2,3,4,5]
Ibrutinib has become a new standard of care for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), MCL, and Waldenstrom macroglobulinemia (WM) [21]
Thirteen (40.6%) patients were categorized into the low Bruton’s tyrosine kinase (BTK) expression group, which was characterized by less than one-quarter positive staining proportion (Figure 1C and 1D), and 19 (59.4%) patients were categorized into the high BTK expression group, which was characteristic of a widely broken and disappeared germinal center (Figure 1E and 1F)

Summary

Introduction

Mantle cell lymphoma (MCL) originates from B lymphocytes in the region of the small lymph node, which accounts for 3% to 10% of non-Hodgkin’s lymphoma (NHL) [1,2,3,4,5]. The genetic characteristics of MCL include t(11;14) (q13;q32) translocation and cyclin D1 (CCND1) overexpression, which usually causes deregulation of the cell cycle at the G1-S phase transition [13]. This translocation is considered to play a primary role in MCL pathogenesis, other carcinogenic events are required for MCL progression [14,15,16,17]. The Bcell receptor (BCR) signaling is crucial for normal Bcell development It regulates multiple biological processes, including cell proliferation, differentiation, apoptosis, and migration [15, 19]. It is necessary to develop highly specific BTK inhibitors for lymphoma treatment

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