Data from <i>MRE11</i> Deficiency Increases Sensitivity to Poly(ADP-ribose) Polymerase Inhibition in Microsatellite Unstable Colorectal Cancers

Abstract

<div>Abstract<p>Microsatellite instability (MSI) is displayed by approximately 15% of colorectal cancers (CRC). Defective DNA mismatch repair generates mutations at repetitive DNA sequences such as those located in the double strand break (DSB) repair gene <i>MRE11</i>. We assessed the mutational status of <i>MRE11</i> in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. Therefore, we hypothesized that deficiency in <i>MRE11</i> may sensitize CRC cells to poly(ADP-ribose) polymerase (PARP-1) inhibition based on the concept of synthetic lethality. We further assessed the activity of the PARP-1 inhibitor, ABT-888, in CRC cell lines and observed preferential cytotoxicity in those MSI cell lines harboring mutations in <i>MRE11</i> compared with both wild-type cell lines and microsatellite stable (MSS) cell lines. A significant correlation between <i>MRE11</i> expression levels and cytotoxicity to ABT-888 at 10 μM was observed (<i>R</i><sup>2</sup> = 0.915, <i>P</i> < 0.001). Using two experimental approaches, including short hairpin RNA knocking down <i>MRE11</i> in the wild-type and MSS cell line SW-480 and a second cell line model transfected with mutant <i>MRE11</i>, we experimentally tried to confirm the role of <i>MRE11</i> in conferring sensitivity to PARP-1 inhibition. Both models led to changes in proliferation in response to ABT-888 at different concentrations, and a drug–response effect was not observed, suggesting a possible contribution of additional genes. We conclude that MSI colorectal tumors deficient in DSB repair secondary to mutation in <i>MRE11</i> show a higher sensitivity to PARP-1 inhibition. Further clinical investigation of PARP-1 inhibitors is warranted in MSI CRCs. <i>Cancer Res; 71(7); 2632–42. ©2011 AACR</i>.</p></div>