ATM Deficiency Sensitizes Mantle Cell Lymphoma Cells to Poly(ADP-Ribose) Polymerase-1 Inhibitors

Abstract

Poly-ADP ribose polymerase-1 (PARP-1) inhibition is toxic to cells with mutations in the breast and ovarian cancer susceptibility genes BRCA1 or BRCA2, a concept, termed synthetic lethality. However, whether this approach is applicable to other human cancers with defects in other DNA repair genes has yet to be determined. The Ataxia-Telangiectasia Mutated (ATM) gene is altered in a number of human cancers including Mantle Cell Lymphoma (MCL). Here, we characterize a panel of MCL cell lines for ATM status and function and investigate the potential for synthetic lethality in MCL in the presence of small molecule inhibitors of PARP-1. We show that Granta-519 and UPN2 cells have low levels of ATM protein, are defective in DNA damage-induced ATM-dependent signaling, are radiation sensitive and have cell cycle checkpoint defects: all characteristics of defective ATM function. Significantly, Granta-519 and UPN2 cells were more sensitive to PARP-1 inhibition, than were the ATM-proficient MCL cell lines examined. Furthermore, the PARP-1 inhibitor olaparib (previously known as AZD2281/KU-0059436) significantly decreased tumour growth and increased overall survival in mice bearing subcutaneous xenografts of ATM-deficient Granta-519 cells, while producing only a modest effect on overall survival of mice bearing xenografts of the ATM-proficient cell line, Z138. Thus, PARP inhibitors have therapeutic potential in the treatment of MCL and the concept of synthetic lethality extends to human cancers with ATM alterations.

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

“…Progression-free survival was signifi cantly longer in the BRCA mutant subgroup (HR 0·27, 95% CI 0·16-0·44, p<0·0001) and LOH high subgroup (HR 0·62, 0·42-0·90, p=0·011) than in the LOH low subgroup (fi gure 2A). 12 month progressionfree survival was higher in the BRCA mutant subgroup (50%, 95% CI 33-65) and LOH high subgroup (28%, 18-39) than in the LOH low subgroup (10%, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The proportionality of hazards assumption was not violated (appendix pp [4][5]15).…”

Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells

“…In addition to BRCA2, previous studies have documented synthetic lethality between PARP inhibition and loss of other HR components, such as BRCA1 (4) and ATM (7,8). In HCC1937 cells, which lack BRCA1 (36) (Fig.…”

“…These DSBs, which are repaired by HR in BRCApositive cells, are presumed to accumulate in BRCA1-or BRCA2-deficient cells, leading to subsequent cell death. Heightened sensitivity to PARP inhibition has also been observed in cells with other genetic lesions that affect HR, including phosphatase and tensin homolog (PTEN) deficiency (5), ataxia telangiectasia mutated (ATM) deficiency (7,8), and Aurora A overexpression (6).Although the preceding studies underscore the importance of PARP1 and HR in maintaining genomic stability, they do not address the role of nonhomologous end joining (NHEJ), an alternate DSB repair modality that directly joins broken ends of DNA with little or no regard for sequence homology (9). NHEJ is initiated when free DNA ends are bound by Ku70 and Ku80, which recruit the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs).…”

“…These DSBs, which are repaired by HR in BRCApositive cells, are presumed to accumulate in BRCA1-or BRCA2-deficient cells, leading to subsequent cell death. Heightened sensitivity to PARP inhibition has also been observed in cells with other genetic lesions that affect HR, including phosphatase and tensin homolog (PTEN) deficiency (5), ataxia telangiectasia mutated (ATM) deficiency (7,8), and Aurora A overexpression (6).…”

“…The role of PARP1 in the DNA damage response sparked interest in the development of PARP inhibitors as potential chemosensitizers for the treatment of cancer (1,2). The more recent observation that PARP inhibition is particularly lethal to cells deficient in homologous recombination (HR) proteins (3)(4)(5)(6)(7)(8) has generated additional excitement in the cancer chemotherapy community. The current explanation for this hypersensitivity focuses on a mechanism (Fig.…”