Premium
Dual blockade of the PI 3K/Akt/ mTOR pathway inhibits posttransplant Epstein‐Barr virus B cell lymphomas and promotes allograft survival
Author(s) -
Sang Adam X.,
McPherson Marla C.,
Ivison Geoffrey T.,
Qu Xiumei,
Rigdon Joseph,
Esquivel Carlos O.,
Krams Sheri M.,
Martinez Olivia M.
Publication year - 2019
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15216
Subject(s) - pi3k/akt/mtor pathway , medicine , transplantation , cancer research , lymphoma , immunology , sirolimus , b cell , epstein–barr virus , virus , biology , antibody , signal transduction , biochemistry
Posttransplant lymphoproliferative disorder ( PTLD ) is a serious complication of organ transplantation that often manifests as Epstein‐Barr virus ( EBV )‐associated B cell lymphomas. Current treatments for PTLD have limited efficacy and can be associated with graft rejection or systemic toxicities. The mTOR inhibitor, rapamycin, suppresses tumor growth of EBV + B cell lymphoma cells in vitro and in vivo ; however, the efficacy is limited and clinical benefits of mTOR inhibitors for PTLD are variable. Here, we show constitutive activation of multiple nodes within the PI 3K/Akt/ mTOR pathway in EBV + PTLD ‐derived cell lines. Inhibition of either PI 3K or Akt, with specific inhibitors CAL ‐101 and MK ‐2206, respectively, diminished growth of EBV + B cell lines from PTLD patients in a dose‐dependent manner. Importantly, rapamycin combined with CAL ‐101 or MK ‐2206 had a synergistic effect in suppressing cell growth as determined by IC 50 isobolographic analysis and Loewe indices. Moreover, these combinations were significantly more effective than rapamycin alone in inhibiting tumor xenograft growth in NOD ‐ SCID mice. Finally, both CAL ‐101 and MK ‐2206 also prolonged survival of heterotopic cardiac allografts in C57 BL /6 mice. Thus, combination therapy with rapamycin and a PI 3K inhibitor, or an Akt inhibitor, can be an efficacious treatment for EBV ‐associated PTLD , while simultaneously promoting allograft survival.