There is a high incidence of genomic aberration of ataxia telangiectasia mutated (ATM) and genes encoding proteins involved in the ATM pathway in mantle cell lymphoma (MCL). It has been shown that poly(ADP‐ribose) polymerase inhibitor (PARPi) strongly enhances the cytotoxicity of agents, causing single‐strand DNA breaks in cells with impaired homologous recombination repair. Here, we show that PARPi AG14361 potentiates the cytotoxicity induced by topotecan treatment in MCL cell lines, which was not dependent on either TP53 or CHEK2 status. Inhibition and/or knockdown of ATM and BRCA2 did not potentiate the cytotoxic effect of treatment with PARPi and topotecan. With loss of function of ATM, other kinases can still mediate activation of ATM substrates as demonstrated by continued phosphorylation of CHEK2 (Thr‐68), although attenuated and delayed. These results suggest that PARPi may enhance the therapeutic efficacy of DNA damaging agents on MCL through TP53‐independent mechanisms without requiring the inhibition of either ATM or BRCA2. Copyright © 2011 John Wiley & Sons, Ltd.