Synergistic induction of apoptosis by combination of BTK and dual mTORC1/2 inhibitors in diffuse large B cell lymphoma

// Scott A. Ezell 1 , Michele Mayo 1 , Teeru Bihani 1 , Suprawee Tepsuporn 1 , Suping Wang 1 , Melissa Passino 1 , Shaun E. Grosskurth 1 , Mike Collins 1 , Julie Parmentier 1 , Corinne Reimer 1 and Kate F. Byth 1 1 AstraZeneca R&D Boston, Waltham, Massachusetts Correspondence: Kate F Byth, email: // Keywords : Ibrutinib, BTK, AZD2014, mTOR, DLBCL Received : May 11, 2014 Accepted : June 5, 2014 Published : June 7, 2014 Abstract Diffuse large B cell lymphoma is generally treated by chemotherapy and there is an unmet medical need for novel targeted therapies or combination therapies. Using in vitro screening, we have identified the combination of ibrutinib, an inhibitor of the tyrosine kinase BTK, and AZD2014, an mTOR catalytic inhibitor, as being highly synergistic in killing ABC-subtype DLBCL cell lines. Simultaneous inhibition of BTK and mTOR causes apoptosis both in vitro and in vivo and results in tumor regression in a xenograft model. We identify two parallel mechanisms that underlie apoptosis in this setting: cooperative inhibition of cap-dependent translation, and the inhibition of an NF-κB/IL10/STAT3 autocrine loop. Combined disruption of these pathways is required for apoptosis. These data represent a rational basis for the dual inhibition of BTK and mTOR as a potential treatment for ABC-subtype DLBCL.