PI3Kδ Inhibition Augments the Efficacy of Rapamycin in Suppressing Proliferation of Epstein−Barr Virus (EBV)+ B Cell Lymphomas

• Published in: American journal of transplantation Vol. 13; no. 8; pp. 2035 - 2043
• Main Authors: Furukawa, S., Wei, L., Krams, S. M., Esquivel, C. O., Martinez, O. M.
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley 01.08.2013
• Subjects: Biological and medical sciences; Blotting, Western; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Synergism; Epstein-Barr virus; Epstein-Barr Virus Infections - drug therapy; Epstein-Barr Virus Infections - etiology; Epstein-Barr Virus Infections - pathology; Epstein−Barr Virus; Hematologic and hematopoietic diseases; Herpesvirus 4, Human - drug effects; Humans; Imidazoles - pharmacology; Infectious diseases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - etiology; Lymphoma, B-Cell - pathology; Lymphoproliferative Disorders - complications; Lymphoproliferative Disorders - pathology; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Medical sciences; mTOR; Multiprotein Complexes - antagonists & inhibitors; Multiprotein Complexes - metabolism; Organ Transplantation - adverse effects; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation - drug effects; PI3kinase/Akt pathway; Postoperative Complications; posttransplant lymphoproliferative disorder; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Quinolines - pharmacology; Sirolimus - pharmacology; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Viral diseases; Antineoplastic agent; Cell proliferation; Sirolimus; Epstein Barr virus; Macrocycle; Posttransplant lymphoproliferative disorder; Lymphoproliferative syndrome; mTOR; Protein synthesis inhibitor; Inhibition; Gammaherpesvirinae; Epstein-Barr Virus; Herpesviridae; Treatment efficiency; Akt protein kinase; PI3kinase/Akt pathway; Lactone; Malignant hemopathy; B-Lymphocyte; Proliferation; Macrolide; Lymphoma; Infection; Virus; Antibiotic; Viral disease; Mammalian target of rapamycin; Immunosuppressive agent; Antibacterial agent; Cancer; posttransplant lymphoproliferative disorder; Epstein−Barr Virus
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.12328

Posttransplant lymphoproliferative disorder (PTLD) continues to be a devastating and potentially life‐threatening complication in organ transplant recipients. PTLD is associated with EBV infection and can result in malignant B cell lymphomas. Here we demonstrate that the PI3K/Akt/mTOR pathway is highly activated in EBV+ B cell lymphoma lines derived from patients with PTLD. Treatment with the mTORC1 inhibitor Rapamycin (RAPA) partially inhibited the proliferation of EBV+ B cell lines. Resistance to RAPA treatment correlated with high levels of Akt phosphorylation. An mTORC1/2 inhibitor and a PI3K/mTOR dual inhibitor suppressed Akt phosphorylation and showed a greater anti‐proliferative effect on EBV+ B lymphoma lines compared to RAPA. EBV+ B cell lymphoma lines expressed high levels of PI3Kδ. We demonstrate that PI3Kδ is responsible for Akt activation in EBV+ B cell lymphomas, and that selective inhibition of PI3Kδ by either siRNA, or a small molecule inhibitor, augmented the anti‐proliferative effect of RAPA on EBV+ B cell lymphomas. These results suggest that PI3Kδ is a novel, potential therapeutic target for the treatment of EBV‐associated PTLD and that combined blockade of PI3Kδ and mTOR provides increased efficacy in inhibiting proliferation of EBV+ B cell lymphomas. The authors demonstrate that targeting PI3Kδ with a small molecule inhibitor can enhance the antiproliferative effect of mTOR inhibitors in the Epstein‐Barr virus positive B cell lymphomas associated with posttransplant lymphoproliferative disorder.