Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma; 40% of patients relapse after a complete response or are refractory to therapy. To survive, the activated B-cell (ABC) subtype of DLBCL relies upon B-cell receptor signaling, which can be modulated by the activity of Bruton tyrosine kinase (BTK). Targeting BTK with ibrutinib, an inhibitor, provides a therapeutic approach for this subtype of DLBCL. However, non-Hodgkin lymphoma is often resistant to ibrutinib or acquires resistance soon after exposure. We explored how this resistance develops. We generated 3 isogenic ibrutinib-resistant DLBCL cell lines and investigated the deregulated pathways known to be associated with tumorigenic properties. Reduced levels of BTK and enhanced phosphatidylinositol 3-kinase (PI3K)/AKT signaling were hallmarks of these ibrutinib-resistant cells. Upregulation of PI3K-β expression was demonstrated to drive resistance in ibrutinib-resistant cells, and resistance was reversed by the blocking activity of PI3K-β/δ. Treatment with the selective PI3K-β/δ dual inhibitor KA2237 reduced both tumorigenic properties and survival-based PI3K/AKT/mTOR signaling of these ibrutinib-resistant cells. In addition, combining KA2237 with currently available chemotherapeutic agents synergistically inhibited metabolic growth. This study elucidates the compensatory upregulated PI3K/AKT axis that emerges in ibrutinib-resistant cells.

Biocev 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Cancer Biology and Genetics OSU Columbus OH

Department of Hematology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Human Sciences OSU Comprehensive Cancer Center Columbus OH; and

Department of Lymphoma and Myeloma The University of Texas MD Anderson Cancer Center Houston TX

Department of Medical Oncology and Hematology All India Institute of Medical Sciences Rishikesh India

Department of Medicine Baylor College of Medicine Houston TX

Division of Hematology Department of Internal Medicine The Ohio State University Columbus OH

Division of Pharmaceutics and Pharmacology College of Pharmacy OSU Columbus OH

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First-in-class inhibitor of HSP110 blocks BCR activation through SYK phosphorylation in diffuse large B-cell lymphoma

mTOR inhibition amplifies the anti-lymphoma effect of PI3Kβ/δ blockage in diffuse large B-cell lymphoma