Targeting Abnormal DNA Repair in Therapy-Resistant Breast Cancers

Tobin, Lisa A.; Robert, Carine; Nagaria, Pratik; Chumsri, Saranya; Twaddell, William S.; Ioffe, Olga B.; Greco, George E.; Brodie, Angela; Tomkinson, Alan E.; Rassool, Feyruz V.

doi:10.1158/1541-7786.mcr-11-0255

Cited by 79 publications

(71 citation statements)

References 38 publications

(48 reference statements)

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“…There is increasing evidence that deregulation of NHEJ is a pathogenic factor in a number of cancers, including breast cancer, chronic myelogenous leukemia (CML), and soft-tissue sarcomas (34)(35)(36)(37)(38). Our results provide new evidence that NHEJ is deregulated in neuroblastoma and provide explanation for the increased propensity of neuroblastoma tumors to harbor pathogenic segmental chromosomal alterations.…”

Section: Discussionsupporting

confidence: 51%

Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma

Newman

Bashllari

et al. 2015

Molecular Cancer Research

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In neuroblastoma, MYCN genomic amplification and segmental chromosomal alterations including 1p or 11q loss of heterozygocity and/or 17q gain are associated with progression and poor clinical outcome. Segmental alterations are the strongest predictor of relapse and result from unbalanced translocations attributable to erroneous repair of chromosomal breaks. Although sequence analysis of affected genomic regions suggests that these errors arise by nonhomologous end-joining (NHEJ) of DNA double-strand breaks (DSB), abnormalities in NHEJ have not been implicated in neuroblastoma pathogenesis. On this basis, the hypothesis that an error-prone mechanism of NHEJ is critical for neuroblastoma cell survival was tested. Plasmid-based DSB repair assays demonstrated efficient NHEJ activity in human neuroblastoma cells with repair products that were error-prone relative to nontransformed cells. Neuroblastoma cells derived from tumorigenic neuroblastic phenotypes had differential DNA repair protein expression patterns compared with nontumorigenic cells. Tumorigenic neuroblastoma cells were deficient in DNA ligase IV (Lig4) and Artemis (DCLRE1C), mediators of canonical NHEJ. Conversely, enzymes required for an error-prone alternative NHEJ pathway (alt-NHEJ), DNA Ligase IIIa (Lig3), DNA Ligase I (Lig1), and PARP1 protein were upregulated. Inhibition of Lig3 and Lig1 led to DSB accumulation and cell death, linking alt-NHEJ to cell survival in neuroblastoma. Neuroblastoma cells demonstrated sensitivity to PARP1 inhibition (PARPi) that paralleled PARP1 expression. In a dataset of human neuroblastoma patient tumors, overexpression of genes encoding alt-NHEJ proteins associated with poor survival.Implications: These findings provide an insight into DNA repair fidelity in neuroblastoma and identify components of the alt-NHEJ pathway as promising therapeutic targets. Mol Cancer Res; 13(3); 470-82. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 51%

Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma

Newman

Bashllari

et al. 2015

Molecular Cancer Research

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“…This strategy is supported by recent findings in artificially selected, therapy-resistant cell lines expressing high levels of PARP1 and Lig3a. 42,43 These cell lines were more sensitive to inhibition of either PARP1 or Lig3a alone or in combination with anti-estrogen therapy compared with control cells.…”

Section: Discussionmentioning

confidence: 99%

Targeting components of the alternative NHEJ pathway sensitizes KRAS mutant leukemic cells to chemotherapy

Hähnel

Enders

Sasca

et al. 2014

Blood

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Key Points• Oncogenic KRAS causes upregulation of components of the alt-NHEJ pathway, thereby promoting genomic instability.• Inhibition of the alt-NHEJ pathway selectively sensitizes KRAS-mutant leukemic cells to cytotoxic agents.Activating KRAS mutations are detected in a substantial number of hematologic malignancies. In a murine T-cell acute lymphoblastic leukemia (T-ALL) model, we previously showed that expression of oncogenic Kras induced a premalignant state accompanied with an arrest in T-cell differentiation and acquisition of somatic Notch1 mutations. These findings prompted us to investigate whether the expression of oncogenic KRAS directly affects DNA damage repair. Applying divergent, but complementary, genetic approaches, we demonstrate that the expression of KRAS mutants is associated with increased expression of DNA ligase 3a, poly(ADP-ribose) polymerase 1 (PARP1), and X-ray repair cross-complementing protein 1 (XRCC1), all essential components of the error-prone, alternative nonhomologous end-joining (alt-NHEJ) pathway. Functional studies revealed delayed repair kinetics, increased misrepair of DNA double-strand breaks, and the preferential use of microhomologous DNA sequences for end joining. Similar effects were observed in primary murine T-ALL blasts. We further show that KRAS-mutated cells, but not KRAS wild-type cells, rely on the alt-NHEJ repair pathway on genotoxic stress. RNA interference-mediated knockdown of DNA ligase 3a abolished resistance to apoptotic cell death in KRAS-mutated cells. Our data indicate that targeting components of the alt-NHEJ pathway sensitizes KRAS-mutated leukemic cells to standard chemotherapeutics and represents a promising approach for inducing synthetic lethal vulnerability in cells harboring otherwise nondruggable KRAS mutations. (Blood. 2014;123(15):2355-2366

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“…More recently, it has been shown that c-Myc, which is a target of the tyrosine kinases, BCR-ABL and FLT3-internal tandem duplication (FLT3-ITD), plays a significant role in the transcriptional activation and expression of DNA ligase III and PARP1, in part via the regulation of micro-RNAs [94]. More recent studies have provided evidence that oestrogen and progesterone receptor positive (ER/PR + ) MCF7 breast cancer cells also display diminished levels of DNA ligase IV, enhanced levels of DNA ligase III, and increased usage of Alt-NHEJ with deletion formation [95].…”

Section: Modulation Of End-joining In Cancer Cellsmentioning

confidence: 99%

“…The ability to exploit the down-regulation of HR by the use of PARP inhibitors is arguably one of the most well rationalised anti-cancer treatments [107,108 ]. The potential for exploiting the enhanced usage of Alt-NHEJ over NHEJ is already underway [95,109]. The recent studies of the use of Pol in this process provide a further therapeutic avenue for therapy of tumours with down-regulated HR [99,100].…”

Section: The Translational Potential Of Understanding These Mechanismsmentioning

confidence: 99%

How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability

Jeggo

Löbrich

2015

Biochemical Journal

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DNA DSBs (double-strand breaks) are a significant threat to the viability of a normal cell, since they can result in loss of genetic material if mitosis or replication is attempted in their presence. Consequently, evolutionary pressure has resulted in multiple pathways and responses to enable DSBs to be repaired efficiently and faithfully. Cancer cells, which are under pressure to gain genomic instability, have a striking ability to avoid the elegant mechanisms by which normal cells maintain genomic stability. Current models suggest that, in normal cells, DSB repair occurs in a hierarchical manner that promotes rapid and efficient rejoining first, with the utilization of additional steps or pathways of diminished accuracy if rejoining is unsuccessful or delayed. In the present review, we evaluate the fidelity of DSB repair pathways and discuss how cancer cells promote the utilization of less accurate processes. Homologous recombination serves to promote accuracy and stability during replication, providing a battlefield for cancer to gain instability. Non-homologous end-joining, a major DSB repair pathway in mammalian cells, usually operates with high fidelity and only switches to less faithful modes if timely repair fails. The transition step is finely tuned and provides another point of attack during tumour progression. In addition to DSB repair, a DSB signalling response activates processes such as cell cycle checkpoint arrest, which enhance the possibility of accurate DSB repair. We consider the ways by which cancers modify and hijack these processes to gain genomic instability.

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Targeting Abnormal DNA Repair in Therapy-Resistant Breast Cancers

Cited by 79 publications

References 38 publications

Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma

Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma

Targeting components of the alternative NHEJ pathway sensitizes KRAS mutant leukemic cells to chemotherapy

How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability

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