title: MRE11 deficiency increases sensitivity to poly(ADP-ribose) polymerase inhibition in microsatellite unstable colorectal cancers.
abstract: 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 MRE11. We assessed the mutational status of MRE11 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 MRE11 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 MRE11 compared with both wild-type cell lines and microsatellite stable (MSS) cell lines. A significant correlation between MRE11 expression levels and cytotoxicity to ABT-888 at 10 μM was observed (R² = 0.915, P < 0.001). Using two experimental approaches, including short hairpin RNA knocking down MRE11 in the wild-type and MSS cell line SW-480 and a second cell line model transfected with mutant MRE11, we experimentally tried to confirm the role of MRE11 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 MRE11 show a higher sensitivity to PARP-1 inhibition. Further clinical investigation of PARP-1 inhibitors is warranted in MSI CRCs.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Vilar
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bartnik
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Stenzel
authors.forename: Leon
authors.initials: L
authors.lastname: Raskin
authors.forename: Jaeil
authors.initials: J
authors.lastname: Ahn
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.forename: Bhramar
authors.initials: B
authors.lastname: Mukherjee
authors.forename: Maria D
authors.initials: MD
authors.lastname: Iniesta
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Morgan
authors.forename: Gad
authors.initials: G
authors.lastname: Rennert
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
mesh_terms: D017766:Acid Anhydride Hydrolases; D001562:Benzimidazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D000076228:MRE11 Homologue Protein; D053842:Microsatellite Instability; D009154:Mutation; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D051135:Rad51 Recombinase / Q000235:genetics; D011995:Recombination, Genetic
chemical_list: D001562:Benzimidazoles; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C121766:MRE11 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes