PARP inhibitors Lord, Christopher J.; Ashworth, Alan
Science,
03/2017, Letnik:
355, Številka:
6330
Journal Article
Recenzirano
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PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a ...century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.
The genetic concept of synthetic lethality has now been validated clinically through the demonstrated efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of cancers in ...individuals with germline loss-of-function mutations in either BRCA1 or BRCA2. Three different PARP inhibitors have now been approved for the treatment of patients with BRCA-mutant ovarian cancer and one for those with BRCA-mutant breast cancer; these agents have also shown promising results in patients with BRCA-mutant prostate cancer. Here, we describe a number of other synthetic lethal interactions that have been discovered in cancer. We discuss some of the underlying principles that might increase the likelihood of clinical efficacy and how new computational and experimental approaches are now facilitating the discovery and validation of synthetic lethal interactions. Finally, we make suggestions on possible future directions and challenges facing researchers in this field.
Synthetic lethality provides a potential mechanistic framework for the therapeutic targeting of genetic and functional deficiencies in cancers and is now being explored widely. The first clinical ...exemplification of synthetic lethality in cancer has been the exploitation of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of cancers with defects in the BRCA1 or BRCA2 tumor suppressor proteins, which are involved in the repair of DNA damage. Although this approach has shown promise, multiple potential resistance mechanisms have been identified. In this Perspective, we discuss these mechanisms and their relevance to the development of selective therapies for BRCA-deficient cancers.
Strategies that motivate agrifood producers to adopt more sustainable practices are a critical component for a sustainable future. This case study examines farmer attitudes to a recently released New ...Zealand agricultural policy aimed at improving freshwater quality by restricting agricultural activities. Our study interprets interviews of nine individuals managing a range of dairy and sheep farming operations to explore how these farmers manage societal expectations of being a ‘good farmer’ in the context of the new regulations. Four themes were developed to capture perceptions of participants: the vested interest of farmers in positive community engagement and being seen as a ‘good’ farmer; the need to manage farms prudently for future generations; the unique geographical and environmental conditions on each farm and their concerns about the lack of acknowledgment of differences across land types in New Zealand; and the unintended consequences of the new regulations for rural communities. Overall, the themes suggest that the way the policy was enacted conflicts with perceptions of a ‘good farmer’ and good farming practice, resulting in identity conflicts for the farming community and reduced motivation to adopt alternative practices.
As cancer cell genomes are unveiled at a breathtaking pace, the genetic principles at play in cancer are emerging in all their complexity, prompting the assessment of classical genetic interaction ...models. Here, we discuss the implications of these findings for cancer progression and heterogeneity and for the development of new therapeutic approaches.
P values and error bars help readers infer whether a reported difference would likely recur, with the sample size n used for statistical tests representing biological replicates, independent ...measurements of the population from separate experiments. We provide examples and practical tutorials for creating figures that communicate both the cell-level variability and the experimental reproducibility.
The genetic concept of synthetic lethality, in which the combination or synthesis of mutations in multiple genes results in cell death, provides a framework to design novel therapeutic approaches to ...cancer. Already there are promising indications, from clinical trials exploiting this concept by using poly(ADP-ribose) polymerase (PARP) inhibitors in patients with germline
BRCA1
or
BRCA2
gene mutations, that this approach could be beneficial. We discuss the biological rationale for BRCA-PARP synthetic lethality, how the synthetic lethal approach is being assessed in the clinic, and how mechanisms of resistance are starting to be dissected. Applying the synthetic lethal concept to target non-
BRCA
-mutant cancers also has clear potential, and we discuss how some of the principles learned in developing PARP inhibitors might also drive the development of additional genetic approaches.
Poly (ADP-ribose) polymerase (PARP) inhibitors elicit antitumour activity in homologous recombination-defective cancers by trapping PARP1 in a chromatin-bound state. How cells process trapped PARP1 ...remains unclear. Using wild-type and a trapping-deficient PARP1 mutant combined with rapid immunoprecipitation mass spectrometry of endogenous proteins and Apex2 proximity labelling, we delineated mass spectrometry-based interactomes of trapped and non-trapped PARP1. These analyses identified an interaction between trapped PARP1 and the ubiquitin-regulated p97 ATPase/segregase. We found that following trapping, PARP1 is SUMOylated by PIAS4 and subsequently ubiquitylated by the SUMO-targeted E3 ubiquitin ligase RNF4, events that promote recruitment of p97 and removal of trapped PARP1 from chromatin. Small-molecule p97-complex inhibitors, including a metabolite of the clinically used drug disulfiram (CuET), prolonged PARP1 trapping and enhanced PARP inhibitor-induced cytotoxicity in homologous recombination-defective tumour cells and patient-derived tumour organoids. Together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 and the response of tumour cells to PARP inhibitors.
The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all ...target the catalytic center of the enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable.
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