Pre-clinical activity of targeting the PI3K/Akt/mTOR pathway in Burkitt lymphoma

// Maria Bhatti 1, 2 , Thomas Ippolito 1 , Cory Mavis 3 , Juan Gu 3 , Mitchell S. Cairo 4 , Megan S. Lim 5 , Francisco Hernandez-Ilizaliturri 3 and Matthew J. Barth 1, 2 1 Department of Pediatric Hematology/Oncology, University at Buffalo, Buffalo, NY, USA 2 Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, NY, USA 3 Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA 4 Department of Pediatrics, Medicine, Pathology, Microbiology and Immunology, Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA 5 Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA Correspondence to: Matthew J. Barth, email: matthew.barth@roswellpark.org Keywords: Burkitt; PI3K; AKT; idelalisib Received: October 26, 2017 Accepted: March 22, 2018 Published: April 24, 2018 ABSTRACT Though outcomes for pediatric Burkitt lymphoma (BL) have improved significantly in recent decades with intensive multi-agent chemotherapy and the addition of rituximab, chemotherapy resistance remains a significant impediment to cure following relapse. Activation of the PI3K/AKT pathway has been implicated in Burkitt lymphomagenesis and increased PI3K/AKT activation has been associated with worse outcomes in adults with aggressive B-cell non-Hodgkin lymphoma (B-NHL). Inhibitors of the PI3K/AKT pathway have been approved for the treatment of refractory indolent B-NHL and continue to be investigated for treatment of aggressive B-NHLs. We investigated the activation of the PI3K/AKT pathway in a cell line model of resistant BL and the ability to target this pathway with small molecule inhibitors in BL cell lines. We found that cell lines resistant to rituximab and chemotherapy exhibited increased activation of PI3K/AKT and that inhibition of AKT or PI3K results in in vitro anti-lymphoma activity. To investigate the role of PI3K/AKT activation on the efficacy of cytotoxic chemotherapy, we exposed cells to inhibitors in combination with chemotherapy and noted a synergistic increase in response to chemotherapy. Overall these findings highlight the role of PI3K/AKT in chemotherapy resistance in BL cells and may represent a tractable therapeutic target.