ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition.

Abstract

BACKGROUND:

Mutations in the DNA damage response (DDR) factors, breast cancer 1 (BRCA1) and BRCA2, sensitize tumor cells to poly(ADP-ribose) polymerase (PARP) inhibitors. The ataxia telangiectasia mutated (ATM) kinase is a key DDR protein whose heterozygous germline mutation is a moderate-risk factor for developing breast cancer. In this study, we examined whether ATM inactivation in breast cancer cell lines confers sensitivity to PARP inhibitors.

METHODS:

Wild-type BRCA1/2 breast cancer cells (i.e., MCF-7 and ZR-75-1 lines) were genetically manipulated to downregulate ATM expression then assayed for cytostaticity/cytotoxicity upon treatment with PARP inhibitors, olaparib and iniparib.

RESULTS:

When ATM-depleted cells and their relative controls were treated with olaparib (a competitive PARP-1/2 inhibitor) and iniparib (a molecule originally described as a covalent PARP-1 inhibitor) a different response to the two compounds was observed. ATM-depletion sensitized both MCF-7 and ZR-75-1 cells to olaparib-treatment, as assessed by short and long survival assays and cell cycle profiles. In contrast, iniparib induced only a mild, ATM-dependent cytostatic effect in MCF-7 cells whereas ZR-75-1 cells were sensitive to this drug, independently of ATM inactivation. These latest results might be explained by recent observations indicating that iniparib acts with mechanisms other than PARP inhibition.

CONCLUSIONS:

These data indicate that ATM-depletion can sensitize breast cancer cells to PARP inhibition, suggesting a potential in the treatment of breast cancers low in ATM protein expression/activity, such as those arising in mutant ATM heterozygous carriers.

• Authors: Maria Saveria Gilardini Montani, Andrea Prodosmo, Venturina Stagni, Dania Merli, Laura Monteonofrio, Veronica Gatti, Maria Pia Gentileschi, Daniela Barilà, Silvia Soddu
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 32 Pg. 95 (Nov 19 2013) ISSN: 1756-9966 [Electronic] England
• PMID: 24252502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• iniparib
• Poly(ADP-ribose) Polymerases
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• olaparib

Topics

• Ataxia Telangiectasia Mutated Proteins (deficiency, genetics, metabolism)
• Benzamides (pharmacology)
• Breast Neoplasms (genetics, metabolism)
• Cell Line, Tumor
• DNA Damage
• DNA Repair
• Female
• Gene Knockdown Techniques
• Humans
• MCF-7 Cells
• Phthalazines (pharmacology)
• Piperazines (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Risk Factors