Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition.

Abstract

ATR is an attractive target in cancer therapy because it signals replication stress and DNA lesions for repair and to S/G2 checkpoints. Cancer-specific defects in the DNA damage response (DDR) may render cancer cells vulnerable to ATR inhibition alone. We determined the cytotoxicity of the ATR inhibitor VE-821 in isogenically matched cells with DDR imbalance. Cell cycle arrest, DNA damage accumulation and repair were determined following VE-821 exposure.Defects in homologous recombination repair (HRR: ATM, BRCA2 and XRCC3) and base excision repair (BER: XRCC1) conferred sensitivity to VE-821. Surprisingly, the loss of different components of the trimeric non-homologous end-joining (NHEJ) protein DNA-PK had opposing effects. Loss of the DNA-binding component, Ku80, caused hypersensitivity to VE-821, but loss of its partner catalytic subunit, DNA-PKcs, did not. Unexpectedly, VE-821 was particularly cytotoxic to human and hamster cells expressing high levels of DNA-PKcs. High DNA-PKcs was associated with replicative stress and activation of the DDR. VE-821 suppressed HRR, determined by RAD51 focus formation, to a greater extent in cells with high DNA-PKcs.Defects in HRR and BER and high DNA-PKcs expression, that are common in cancer, confer sensitivity to ATR inhibitor monotherapy and may be developed as predictive biomarkers for personalised medicine.

• Authors: Fiona K Middleton, Miranda J Patterson, Claire J Elstob, Sarah Fordham, Ashleigh Herriott, Mark A Wade, Aiste McCormick, Richard Edmondson, Felicity E B May, James M Allan, John R Pollard, Nicola J Curtin
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 32 Pg. 32396-409 (Oct 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26486089 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide
• Antineoplastic Agents
• MYC protein, human
• Nuclear Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-myc
• Pyrazines
• Sulfones
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• DNA-Activated Protein Kinase
• PRKDC protein, human
• DNA Repair Enzymes

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors, genetics, metabolism)
• Brain Neoplasms (drug therapy, enzymology, genetics, pathology)
• CHO Cells
• Cell Line, Tumor
• Computational Biology
• Cricetinae
• Cricetulus
• DNA Damage
• DNA Repair (genetics)
• DNA Repair Enzymes (genetics, metabolism)
• DNA-Activated Protein Kinase (genetics, metabolism)
• Databases, Genetic
• Dose-Response Relationship, Drug
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Glioblastoma (drug therapy, enzymology, genetics, pathology)
• Humans
• Molecular Targeted Therapy
• Nuclear Proteins (genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Pyrazines (pharmacology)
• Signal Transduction (drug effects)
• Sulfones (pharmacology)
• Time Factors
• Transfection