Poly (ADP-ribose) polymerase inhibitor LT-626: Sensitivity correlates with MRE11 mutations and synergizes with platinums and irinotecan in colorectal cancer cells.
Some colorectal cancers (CRC) display microsatellite instability (MSI) leading to mutations in genes such as MRE11. The aim of this study was to determine whether MSI or MRE11 mutational status correlates with sensitivity to the PARP inhibitor LT-626 and whether LT-626 synergizes with DNA-damaging chemotherapeutic agents. CRC cells harboring biallelic MRE11 mutations were more sensitive to LT-626 and stable overexpression or knock-down of MRE11 in cell lines correlated with sensitivity. Synergism was evident between LT-626 and cisplatin, oxaliplatin and SN-38 suggesting that PARP inhibitors in combination with DNA damaging agents may be a successful strategy for treatment of CRC.
Division of Oncology, Stanford University School of Medicine, Stanford, CA, United States.
Lisa A
LA
McPherson
BioMarin Pharmaceutical Inc., Novato, CA, United States.
Yuqiao
Y
Shen
Division of Oncology, Stanford University School of Medicine, Stanford, CA, United States. Electronic address: jmf@stanford.edu.
James M
JM
Ford
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000201:enzymology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004357:Drug Synergism; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D000076228:MRE11 Homologue Protein; D009154:Mutation; D010793:Phthalazines / Q000737:chemistry / Q000494:pharmacology*; D010984:Platinum / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D060888:Real-Time Polymerase Chain Reaction
C587013:5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido(4,3,2-de)phthalazin-3(7H)-one; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D006575:Heterocyclic Compounds, 3-Ring; C121766:MRE11 protein, human; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D010984:Platinum; D000077146:Irinotecan; D000076228:MRE11 Homologue Protein; D002945:Cisplatin; D002166:Camptothecin
Colorectal cancer; DNA damage; MRE11; MSI; PARP inhibitors