Olaparib Induced Moderate Killing of ATM-Deficient Mantle Cell Lymphoma Cells In Vitro and In Vivo

Abstract

The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as and Mantle Cell Lymphoma (MCL) and is associated with defective apoptosis, especially in response to standard cytotoxic chemotherapy. ATM deficient cells exhibit impaired homologous recombination and the inability to correct double strand DNA breaks. Inhibition of poly (ADPribose) Polymerase (PARP), which is required for DNA double strand break repair, has been shown to sensitize ATM-deficient tumor cells to killing. We investigated in vitro and in vivo sensitivity to the PARP inhibitor olaparib in the ATM deficient mantle cell lymphoma cell line Granta-519. Olaparib monotherapy and in combination with cisplatin or bendamustine confirmed decreased proliferation in vitro. A Nonobese Diabetic/Severe Combined Immunodeficient (NOD/SCID) murine xenograft model with the Granta-519 cell line did not result in a significantly reduced tumor load following treatment with olaparib in vivo.