Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53

Chris T Williamson,David Gilley,Susan P Lees‐Miller,Jeffrey D Hamill,Eiji Kubota,Bruce C Mckay,Alexander Klimowicz,Michelle Dean,Liren Tu,Anthony M Magliocco,Ruiqiong Ye,Huong Muzik,D Gwyn Bebb

doi:10.1002/emmm.201200229

Abstract

Poly-ADP ribose polymerase (PARP) inhibitors have shown promise in the treatment of human malignancies characterized by deficiencies in the DNA damage repair proteins BRCA1 and BRCA2 and preclinical studies have demonstrated the potential effectiveness of PARP inhibitors in targeting ataxia-telangiectasia mutated (ATM)-deficient tumours. Here, we show that mantle cell lymphoma (MCL) cells deficient in both ATM and p53 are more sensitive to the PARP inhibitor olaparib than cells lacking ATM function alone. In ATM-deficient MCL cells, olaparib induced DNA-PK-dependent phosphorylation and stabilization of p53 as well as expression of p53-responsive cell cycle checkpoint regulators, and inhibition of DNA-PK reduced the toxicity of olaparib in ATM-deficient MCL cells. Thus, both DNA-PK and p53 regulate the response of ATM-deficient MCL cells to olaparib. In addition, small molecule inhibition of both ATM and PARP was cytotoxic in normal human fibroblasts with disruption of p53, implying that the combination of ATM and PARP inhibitors may have utility in targeting p53-deficient malignancies.

Highlights

Synthetic lethality using poly-ADP ribose polymerase (PARP) inhibitors has emerged as a new potential therapeutic strategy to exploit tumour-specific genetic alterations
Since the ataxia-telangiectasia mutated (ATM) gene is frequently altered through mutation or deletion in mantle cell lymphoma (MCL) (Schaffner et al, 2000), the use of PARP inhibitors to induce synthetic lethality is an attractive proposition in this disease
We show that MCL cell lines and normal human fibroblasts with inactivation or mutation of both ATM and p53 are more sensitive to the PARP inhibitor olaparib than the same cells with inactivation or mutation of ATM alone

Summary

Introduction

Synthetic lethality using poly-ADP ribose polymerase (PARP) inhibitors has emerged as a new potential therapeutic strategy to exploit tumour-specific genetic alterations. Synthetic lethality is defined as the premise, whereby, deletion of one of two genes independently has no effect on cellular viability, whereas, simultaneous loss of both genes is lethal (Kaelin, 2005). The utility of this approach was first demonstrated when cells with mutations in the breast and ovarian susceptibility genes BRCA1 and BRCA2 were shown to be extremely sensitive to small molecule inhibitors of the DNA single strand break (SSB) sensing protein PARP-1 (Bryant et al, 2005; Farmer et al, 2005). Subsequent experiments revealed that additional proteins share a synthetic lethal interaction with PARP, including the DNA damage activated protein kinase ataxia-telangiectasia mutated (ATM; Lord et al, 2008; Turner et al, 2008)

Methods

Results

Conclusion