Opinion: PARP inhibitors in cancer-what do we still need to know?

PARP inhibitors (PARPi) have been demonstrated to exhibit profound anti-tumour activity in individuals whose cancers have a defect in the homologous recombination DNA repair pathway. Here, we describe the current consensus as to how PARPi work and how drug resistance to these agents emerges. We discuss the need to refine the current repertoire of clinical-grade companion biomarkers to be used with PARPi, so that patient stratification can be improved, the early emergence of drug resistance can be detected and dose-limiting toxicity can be predicted. We also highlight current thoughts about how PARPi resistance might be treated.

The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin.

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.

Sirtuin inhibition is synthetic lethal with BRCA1 or BRCA2 deficiency.

PARP enzymes utilise NAD+ as a co-substrate for their enzymatic activity. Inhibition of PARP1 is synthetic lethal with defects in either BRCA1 or BRCA2. In order to assess whether other genes implicated in NAD+ metabolism were synthetic lethal with BRCA1 or BRCA2 gene defects, we carried out a genetic screen, which identified a synthetic lethality between BRCA1 and genetic inhibition of either of two sirtuin (SIRT) enzymes, SIRT1 or SIRT6. This synthetic lethal interaction was replicated using small-molecule SIRT inhibitors and was associated with replication stress and increased cellular PARylation, in contrast to the decreased PARylation associated with BRCA-gene/PARP inhibitor synthetic lethality. SIRT/BRCA1 synthetic lethality was reversed by genetic ablation of either PARP1 or the histone PARylation factor-coding gene HPF1, implicating PARP1/HPF1-mediated serine ADP-ribosylation as part of the mechanistic basis of this synthetic lethal effect. These observations suggest that PARP1/HPF1-mediated serine ADP-ribosylation, when driven by SIRT inhibition, can inadvertently inhibit the growth of BRCA-gene mutant cells.

PARP Inhibitors - Trapped in a Toxic Love Affair.

It is often the case that when an investigational cancer drug first enters clinical development, its precise mechanism of action is unclear. This was the case for PARP inhibitors (PARPi) used to treat homologous recombination-defective cancers. In 2012, nearly a decade after the first PARPi entered clinical development, work from Murai and colleagues demonstrated that clinical PARPi not only inhibit the catalytic activity of PARP1, PARylation, but also "trap" PARP1 on DNA; this latter effect being responsible for much of the tumor cell cytotoxicity caused by these drugs. We discuss how this work not only changed our understanding about how PARPi work, but also stimulated subsequent dissection of how PARP1 carries out its normal function in the absence of inhibitor.See related article by Murai and colleagues, Cancer Res 2012;72:5588-99.

Spheres of Influence: A Walzerian Approach to Business Ethics.

Michael Walzer is one of the most distinguished political philosophers and social critics of this century. His ideas have had great import and influence in political philosophy and political discussion, yet very few of his ideas have been incorporated explicitly into the business ethics literature. We argue that Walzer's work provides an important conceptual canvas for business ethics scholars that has not been adequately explored. Scholars in business ethics often borrow from political theory and philosophy to generate new insights and develop new substantive contributions. Many valuable theoretical resources are already used extensively-particularly Aristotle, Kant, Marx and a variety of utilitarian philosophers. Walzer offers another set of resources to bring to the conversation of what business ethics is and how business ethicists add value. This paper provides an opportunity to delve further into Walzer's writings, particularly themes that are tied to business ethics, and to illustrate how his ideas can be extended to reshape our understanding of the field and develop new perspectives on ethical issues in commerce.

Structural basis for allosteric PARP-1 retention on DNA breaks.

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.

When worlds collide: medicine, business, the Affordable Care Act and the future of health care in the U.S.

The dialogue about the future of health care in the US has been impeded by flawed conceptions about medicine and business. The present paper re-examines some of the underlying assumptions about both medicine and business, and uses more nuanced readings of both terms to frame debates about the ACA and the emerging health care environment.

Subperiosteal aneurysmal bone cyst with associated bone marrow oedema: an unusual appearance.

A case of a subperiosteal aneurysmal bone cyst with adjacent bone marrow oedema is presented. Aneurysmal bone cysts have been well documented in the published literature; however, relatively few have been observed in a subperiosteal location, and associated bone marrow oedema in the absence of a demonstrable pathological fracture is a rare finding. Aneursymal bone cyst should be considered in the differential diagnosis of subperiosteal bone lesions and may be associated with bone marrow oedema.

Ethics and incentives: an evaluation and development of stakeholder theory in the health care industry.

This paper utilizes a qualitative case study of the health care industry and a recent legal case to demonstrate that stakeholder theory's focus on ethics, without recognition of the effects of incentives, severely limits the theory's ability to provide managerial direction and explain managerial behavior. While ethics provide a basis for stakeholder prioritization, incentives influence whether managerial action is consistent with that prioritization. Our health care examples highlight this and other limitations of stakeholder theory and demonstrate the explanatory and directive power added by the inclusion of the interactive effects of ethics and incentives in stakeholder ordering.