title: PI3Kδ inhibition augments the efficacy of rapamycin in suppressing proliferation of Epstein-Barr virus (EBV)+ 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 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.
authors.affiliation: Division of Abdominal Transplantation, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Furukawa
authors.forename: L
authors.initials: L
authors.lastname: Wei
authors.forename: S M
authors.initials: SM
authors.lastname: Krams
authors.forename: C O
authors.initials: CO
authors.lastname: Esquivel
authors.forename: O M
authors.initials: OM
authors.lastname: Martinez
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004854:Herpesvirus 4, Human / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000150:complications* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D016377:Organ Transplantation / Q000009:adverse effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011183:Postoperative Complications; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007093:Imidazoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C531198:dactolisib
keywords: Epstein−Barr Virus; PI3kinase/Akt pathway; mTOR; posttransplant lymphoproliferative disorder