PI3K Inhibition Augments the Efficacy of Rapamycin in Suppressing Proliferation of Epstein-Barr Virus (EBV) plus B Cell Lymphomas

Abstract

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 PI3Kd. We demonstrate that PI3Kd is responsible for Akt activation in EBV+ B cell lymphomas, and that selective inhibition of PI3Kd by either siRNA, or a small molecule inhibitor, augmented the anti-proliferative effect of RAPA on EBV+ B cell lymphomas. These results suggest that PI3Kd is a novel, potential therapeutic target for the treatment of EBV-associated PTLD and that combined blockade of PI3Kd and mTOR provides increased efficacy in inhibiting proliferation of EBV+ B cell lymphomas.

View details for DOI 10.1111/ajt.12328

View details for Web of Science ID 000322330000013

View details for PubMedID 23841834