Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase

  title={Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase},
  author={Helen E. Bryant and Niklas Schultz and Huw D. Thomas and Kayan M. Parker and Dan Flower and Elena Lopez and Suzanne Kyle and Mark Meuth and Nicola J. Curtin and Thomas Helleday},
Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours. Here, we show that PARP inhibitors trigger γ-H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient… 

Synthetic lethality between BRCA1 deficiency and poly(ADP-ribose) polymerase inhibition is modulated by processing of endogenous oxidative DNA damage

While BRCA1-depleted or -mutated cells were hypersensitive to the clinically approved PARPi olaparib, its toxicity was significantly attenuated by treatment with reactive oxygen species scavengers, growth under hypoxic conditions or chemical OGG1 inhibition.

Poly(ADP-ribose) polymerase is hyperactivated in homologous recombination-defective cells.

It is reported that PARP inhibitor-resistant BRCA2-mutant cells revert back to normal levels of PARP activity, and it is speculated that the reason for the sensitivity of HR-defective cells to PARP inhibitors is related to the hyperactivated PARP1 in these cells.

Identification of regulators of poly-ADP-ribose polymerase (PARP) inhibitor response through complementary CRISPR knockout and activation screens

This work provides a comprehensive set of putative biomarkers that serve to better understand and predict PARPi response, and identifies a novel pathway of PARPi resistance in BRCA2-deficient cells.

Poly(ADP-ribose) Polymerase (PARP-1) in Homologous Recombination and as a Target for Cancer Therapy

Although PARP-1 appears not to be required for homologous recombination itself, it regulates the process through its involvement in the repair of DNA single-strand breaks (SSBs), which triggers homological recombination for replication restart.

The chromatin remodeler ALC1 underlies resistance to PARP inhibitor treatment.

It is concluded that ALC1-dependent PARP1 mobilization is a key step underlying PARP inhibitor resistance.

Molecular Pathways: Targeting PARP in Cancer Treatment

It is imperative that future development of PARP inhibitors take a more refined approach, identifying the unique subset of patients that would most benefit from these agents, determining the optimal time for use, and identifying the optimal combination partner in any particular setting.

Successes and Challenges of PARP Inhibitors in Cancer Therapy

A model was proposed in which PARP inhibition causes unrepaired SSBs, which are subsequently converted to DSBs, leading to synthetic lethality in BRCA-deficient cells treated with PARP inhibitors.

Current status of poly(ADP-ribose) polymerase inhibitors and future directions

Preclinical and clinical data for PARP inhibitors are summarized, their potential for future applications to treat various malignancies are discussed and potential long-term side effects and suitable biomarkers for predicting efficacy and mechanisms of clinical resistance are in discussion.

Enhancing synthetic lethality of PARP-inhibitor and cisplatin in BRCA-proficient tumour cells with hyperthermia

The results in HR-proficient cell lines suggest that PARP1-i combined with thermochemotherapy can be a promising clinical approach for all tumors independent of HR status.



Ablation of PARP-1 does not interfere with the repair of DNA double-strand breaks, but compromises the reactivation of stalled replication forks

Data indicate that PARP-1 is dispensable in HR induced by DSBs, but is involved in the repair and reactivation of stalled replication forks.

Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination.

The data suggest that PARP-1 controls DNA damage recognised by HR and that it is not involved in executing HR as such.

PARP is important for genomic stability but dispensable in apoptosis.

Although PARP is specifically cleaved during apoptosis, cells lacking this molecule apoptosed normally in response to treatment with anti-Fas, tumor neurosis factor alpha, gamma-irradiation, and dexamethasone, indicating thatPARP is dispensable in apoptosis and that PARP-/- thymocytes are not hypersensitive to ionizing radiation.

Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy

BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis, illustrating how different pathways cooperate to repair damage.

Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells.

Results demonstrate that PARP is a survival factor playing an essential and positive role during DNA damage recovery, and inactivated both alleles by gene targeting in mice.

A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage.

The data demonstrate that PARP-1 is required for the assembly or stability of XRCC1 nuclear foci after oxidative DNA damage and suggest that the formation of these foci is mediated via interaction with poly (ADP-ribose).

Loss of poly(ADP‐ribose) polymerase‐1 causes increased tumour latency in p53‐deficient mice

The generation of doubly null mutant mice was reported and it was found that tumour‐free survival of parp‐1‐/−p53−/− mice increased by 50% and iNOS expression and nitrite release were dramatically reduced in the parp-1‐1−/+p53-/−− mice compared with par p‐1+/+p53‐/+ mice.

Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361.

AG14361 is, to the authors' knowledge, the first high-potency PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer.

Brca2 (XRCC11) Deficiency Results in Radioresistant DNA Synthesis and a Higher Frequency of Spontaneous Deletions

It is shown that the radiosensitive Chinese hamster cell mutant (V-C8) of group XRCC11 is defective in the breast cancer susceptibility gene Brca2, which causes hypersensitivity to various DNA-damaging agents with an extreme sensitivity toward interstrand DNA cross-linking agents.

Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro

It would appear that PARP is not involved in the cellular response to etoposide-mediated DNA damage, and PARP inhibitors may be potentially useful in combination with topoisomerase I inhibitor anticancer chemotherapy.