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

Maria Bhatti,Mitchell S Cairo,Juan Gu,Francisco Hernandez-Ilizaliturri,Megan S Lim,Thomas Ippolito,Matthew J Barth,Cory Mavis

doi:10.18632/oncotarget.25072

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.

Highlights

Burkitt lymphoma (BL) is an aggressive form of B-cell non-Hodgkin lymphoma (NHL) and is the most common type of NHL in children
In a previously reported phosphoproteomic analysis of parental Raji cells compared to rituximab-chemotherapy resistant Raji 4RH cells, the B-cell receptor pathway was one of the top pathways with significant differential phosphorylation including differential phosphorylation of several proteins both up and downstream of PI3K and Akt associated with PI3K/Akt pathway activation (Figure 1D)
These findings indicated a possible role of increased activation of the PI3K/Akt/mTOR pathway in the chemotherapy resistance observed in our resistant BL cells suggesting that targeting this pathway may be therapeutically relevant in BL

Summary

Introduction

Burkitt lymphoma (BL) is an aggressive form of B-cell non-Hodgkin lymphoma (NHL) and is the most common type of NHL in children. Multiagent chemotherapy regimens, survival rates for childhood BL have improved significantly in recent decades. The therapy is quite toxic with high rates of acute toxicity including mucositis and infections. 2% of children with BL die from toxic complications of therapy [3,4,5]. In the small percentage of children who develop relapsed or refractory disease, the prognosis is much grimmer with long term survival achieved in only 20–30% of children following further intensified therapy, generally including either autologous or allogeneic hematopoietic stem cell transplant, necessitating the development of novel therapeutic approaches in an attempt to both decrease toxicity in up-front therapy and prolong survival in relapsed/refractory disease [6,7,8,9]

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Conclusion