Mantle cell lymphoma (MCL) is an aggressive and incurable malignant disease. 
Despite of general chemotherapy, relapse and mortality are common, highlighting 
the need for the development of novel targeted drugs or combination of 
therapeutic regimens. Recently, several drugs that target the B-cell receptor 
(BCR) signaling pathway, especially the Bruton's tyrosine kinase (BTK) inhibitor 
ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory 
patients, which indicate that pharmacological inhibition of BCR pathway holds 
promise in MCL treatment. Here, we have developed a novel irreversible BTK 
inhibitor, PLS-123, that has more potent and selective anti-tumor activity than 
ibrutinib in vitro and in vivo. Using in vitro screening, we discovered that the 
combination of PLS-123 and the mammalian target of rapamycin (mTOR) inhibitor 
everolimus exert synergistic activity in attenuating proliferation and motility 
of MCL cell lines. Simultaneous inhibition of BTK and mTOR resulted in marked 
induction of apoptosis and cell cycle arrest in the G1 phase, which were 
accompanied by upregulation of pro-apoptotic proteins (cleaved Caspase-3, 
cleaved PARP and Bax), repression of anti-apoptotic proteins (Mcl-1, Bcl-xl and 
XIAP), and downregulation of regulators of the G1/S phase transition (CDK2, 
CDK4, CDK6 and Cyclin D1). Gene expression profile analysis revealed 
simultaneous treatment with these agents led to inhibition of the JAK2/STAT3, 
AKT/mTOR signaling pathways and SGK1 expression. Finally, the anti-tumor and 
pro-apoptotic activities of combination strategy have also been demonstrated 
using xenograft mice models. Taken together, simultaneous suppression of BTK and 
mTOR may be indicated as a potential therapeutic modality for the treatment of 
MCL.