The Bruton tyrosine kinase (BTK) inhibitor PCI‐32765 synergistically increases proteasome inhibitor activity in diffuse large‐B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib |
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Authors: | Girija Dasmahapatra Hiral Patel Paul Dent Richard I Fisher Jonathan Friedberg Steven Grant |
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Institution: | 1. Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA;2. Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA;3. Department of Biochemistry, Virginia Commonwealth University, Richmond, VA, USA;4. Department of Molecular and Human Genetics, Virginia Commonwealth University, Richmond, VA, USA;5. Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA;6. Division of Hematology Oncology, University of Rochester Medical Center and the James P. Wilmot Cancer Center, Rochester, NY, USA;7. Correspondence: Dr. Steven Grant, Division of Hematology/Oncology, Virginia Commonwealth University, Room 234, Goodwin Research Building, 401 College Street, Richmond, VA 23298, USA.;8. E‐mail: stgrant@vcu.edu |
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Abstract: | Interactions between the Bruton tyrosine kinase (BTK) inhibitor PCI‐32765 and the proteasome inhibitor (bortezomib) were examined in diffuse large‐B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells, including those highly resistant to bortezomib. Co‐administration of PCI‐32765/bortezomib synergistically increased mitochondrial injury and apoptosis in germinal centre‐ or activated B‐cell‐like‐DLBCL cells and in MCL cells. These events were accompanied by marked AKT and nuclear factor (NF)‐κB (NFKB1) inactivation, down‐regulation of Mcl‐1 (MCL1), Bcl‐xL (BCL2L1), and XIAP, and enhanced DNA damage (e.g., γH2A.X formation) and endoplasmic reticulum (ER) stress. Similar interactions were observed in highly bortezomib‐resistant DLBCL and MCL cells, and in primary DLBCL cells. In contrast, PCI‐32765/bortezomib regimens displayed minimal toxicity toward normal CD34+ bone marrow cells. Transfection of DLBCL cells with a constitutively active AKT construct attenuated AKT inactivation and significantly diminished cell death, whereas expression of an NF‐κB “super‐repressor” (IκBαser34/36) increased both PCI‐32765 and bortezomib lethality. Moreover, cells in which the ER stress response was disabled by a dominant‐negative eIF2α construct were resistant to this regimen. Finally, combined exposure to PCI‐32765 and bortezomib resulted in more pronounced and sustained reactive oxygen species (ROS) generation, and ROS scavengers significantly diminished lethality. Given promising early clinical results for PCI‐32765 in DLBCL and MCL, a strategy combining BTK/proteasome inhibitor warrants attention in these malignancies. |
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Keywords: | PCI‐32765 bortezomib bruton tyrosine kinase diffuse large‐B cell lymphoma mantle cell lymphoma |
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