Poly (ADP-ribose) polymerase inhibitor LT-626: Sensitivity correlates with MRE11 mutations and synergizes with platinums and irinotecan in colorectal cancer cells

Lisa A McPherson; Yuqiao Shen; James M Ford

doi:10.1016/j.canlet.2013.10.034

Poly (ADP-ribose) polymerase inhibitor LT-626: Sensitivity correlates with MRE11 mutations and synergizes with platinums and irinotecan in colorectal cancer cells

Cancer Lett. 2014 Feb 28;343(2):217-23. doi: 10.1016/j.canlet.2013.10.034. Epub 2013 Nov 9.

Authors

Lisa A McPherson¹, Yuqiao Shen², James M Ford³

Affiliations

¹ Division of Oncology, Stanford University School of Medicine, Stanford, CA, United States.
² BioMarin Pharmaceutical Inc., Novato, CA, United States.
³ Division of Oncology, Stanford University School of Medicine, Stanford, CA, United States. Electronic address: jmf@stanford.edu.

PMID: 24215868
DOI: 10.1016/j.canlet.2013.10.034

Abstract

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.

Keywords: Colorectal cancer; DNA damage; MRE11; MSI; PARP inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Blotting, Western
Camptothecin / analogs & derivatives*
Camptothecin / pharmacology
Cell Line, Tumor
Cisplatin / pharmacology
Colorectal Neoplasms / enzymology*
DNA-Binding Proteins / genetics*
Drug Synergism
Heterocyclic Compounds, 3-Ring / chemistry
Heterocyclic Compounds, 3-Ring / pharmacology*
Humans
Inhibitory Concentration 50
Irinotecan
MRE11 Homologue Protein
Mutation
Phthalazines / chemistry
Phthalazines / pharmacology*
Platinum / pharmacology*
Poly(ADP-ribose) Polymerase Inhibitors*
Real-Time Polymerase Chain Reaction

Substances

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
Antineoplastic Agents
DNA-Binding Proteins
Heterocyclic Compounds, 3-Ring
MRE11 protein, human
Phthalazines
Poly(ADP-ribose) Polymerase Inhibitors
Platinum
Irinotecan
MRE11 Homologue Protein
Cisplatin
Camptothecin