期刊
AGING-US
卷 13, 期 17, 页码 21102-21121出版社
IMPACT JOURNALS LLC
关键词
BGB-3111; Bruton's tyrosine kinase; bortezomib; mantle cell lymphoma
资金
- Natural Science Foundation of Tianjin [19JCYBJC26500, 18JCZDJC45100]
- National Natural Science Foundation of China [81770213, 81670184]
- National Key New Drug Creation Special Programs [2017ZX09304-021, 2018ZX09201015]
- Clinical Oncology Research Fund of CSCO [Y-XD2019-162]
BGB-3111 demonstrates significant anti-cancer effects in BTK-expressing MCL cells, and when combined with bortezomib, it enhances these effects and improves safety. This combination therapy could be a potential therapeutic strategy for MCL patients.
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 I kappa B alpha 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.
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