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Article: Exploiting Cancer Synthetic Lethality in Cancer-Lessons Learnt from PARP Inhibitors.

Pettitt, Stephen J / Ryan, Colm J / Lord, Christopher J

2023 Volume 186, Page(s) 13–23

Abstract: PARP inhibitors now have proven utility in the treatment of homologous recombination (HR) defective cancers. These drugs, and the synthetic lethality effect they exploit, have not only taught us how to approach the treatment of HR defective cancers but ... ...

Abstract	PARP inhibitors now have proven utility in the treatment of homologous recombination (HR) defective cancers. These drugs, and the synthetic lethality effect they exploit, have not only taught us how to approach the treatment of HR defective cancers but have also illuminated how resistance to a synthetic lethal approach can occur, how cancer-associated synthetic lethal effects are perhaps more complex than we imagine, how the better use of biomarkers could improve the success of treatment and even how drug resistance might be targeted. Here, we discuss some of the lessons learnt from the study of PARP inhibitor synthetic lethality and how these lessons might have wider application. Specifically, we discuss the concept of synthetic lethal penetrance, phenocopy effects in cancer such as BRCAness, synthetic lethal resistance, the polygenic and complex nature of synthetic lethal interactions, how evolutionary double binds could be exploited in treatment as well as future horizons for the field.
MeSH term(s)	Humans ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Synthetic Lethal Mutations ; Neoplasms/drug therapy ; Antineoplastic Agents/therapeutic use
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; Antineoplastic Agents
Language	English
Publishing date	2023-11-17
Publishing country	United States
Document type	Journal Article
ISSN	0927-3042
ISSN	0927-3042
DOI	10.1007/978-3-031-30065-3_2
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Article ; Online: PARP Inhibitors - Trapped in a Toxic Love Affair.

Krastev, Dragomir B / Wicks, Andrew J / Lord, Christopher J

Cancer research

2021 Volume 81, Issue 22, Page(s) 5605–5607

Abstract: 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, ... ...

Abstract	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.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Homologous Recombination ; Humans ; Love ; Neoplasms/drug therapy ; Neoplasms/genetics ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
Chemical Substances	Antineoplastic Agents ; Poly(ADP-ribose) Polymerase Inhibitors
Language	English
Publishing date	2021-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-21-3201
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Article ; Online: Resistance to DNA repair inhibitors in cancer.

Baxter, Joseph S / Zatreanu, Diana / Pettitt, Stephen J / Lord, Christopher J

Molecular oncology

2022 Volume 16, Issue 21, Page(s) 3811–3827

Abstract: The DNA damage response (DDR) represents a complex network of proteins which detect and repair DNA damage, thereby maintaining the integrity of the genome and preventing the transmission of mutations and rearranged chromosomes to daughter cells. Faults ... ...

Abstract	The DNA damage response (DDR) represents a complex network of proteins which detect and repair DNA damage, thereby maintaining the integrity of the genome and preventing the transmission of mutations and rearranged chromosomes to daughter cells. Faults in the DDR are a known driver and hallmark of cancer. Furthermore, inhibition of DDR enzymes can be used to treat the disease. This is exemplified by PARP inhibitors (PARPi) used to treat cancers with defects in the homologous recombination DDR pathway. A series of novel DDR targets are now also under pre-clinical or clinical investigation, including inhibitors of ATR kinase, WRN helicase or the DNA polymerase/helicase Polθ (Pol-Theta). Drug resistance is a common phenomenon that impairs the overall effectiveness of cancer treatments and there is already some understanding of how resistance to PARPi occurs. Here, we discuss how an understanding of PARPi resistance could inform how resistance to new drugs targeting the DDR emerges. We also discuss potential strategies that could limit the impact of these therapy resistance mechanisms in cancer.
MeSH term(s)	Humans ; DNA Repair ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Neoplasms/genetics ; DNA Damage ; Mutation
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors
Language	English
Publishing date	2022-06-05
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.13224
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Article ; Online: Systemic Therapy for Hereditary Breast Cancers.

Harvey-Jones, Elizabeth J / Lord, Christopher J / Tutt, Andrew N J

Hematology/oncology clinics of North America

2022 Volume 37, Issue 1, Page(s) 203–224

Abstract: Approximately 5% to 10% of all breast cancers are hereditary; many of which are caused by pathogenic variants in genes required for homologous recombination, including BRCA1 and BRCA2. Here we discuss systemic treatment for such breast cancers, including ...

Abstract	Approximately 5% to 10% of all breast cancers are hereditary; many of which are caused by pathogenic variants in genes required for homologous recombination, including BRCA1 and BRCA2. Here we discuss systemic treatment for such breast cancers, including approved chemotherapeutic approaches and also targeted treatment approaches using poly-(ADP ribose) polymerase inhibitors. We also discuss experimental approaches to treating hereditary breast cancer, including new small molecule DNA repair inhibitors and also immunomodulatory agents. Finally, we discuss how drug resistance emerges in patients with hereditary breast cancer, how this might be delayed or prevented, and how biomarker-adapted treatment is molding the future management of hereditary breast cancer.
MeSH term(s)	Humans ; Female ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Genes, BRCA2 ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; DNA Repair
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors
Language	English
Publishing date	2022-11-23
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	93115-9
ISSN	1558-1977 ; 0889-8588
ISSN (online)	1558-1977
ISSN	0889-8588
DOI	10.1016/j.hoc.2022.08.018
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Article ; Online: Complex synthetic lethality in cancer.

Ryan, Colm J / Devakumar, Lovely Paul Solomon / Pettitt, Stephen J / Lord, Christopher J

Nature genetics

2023 Volume 55, Issue 12, Page(s) 2039–2048

Abstract: The concept of synthetic lethality has been widely applied to identify therapeutic targets in cancer, with varying degrees of success. The standard approach normally involves identifying genetic interactions between two genes, a driver and a target. In ... ...

Abstract	The concept of synthetic lethality has been widely applied to identify therapeutic targets in cancer, with varying degrees of success. The standard approach normally involves identifying genetic interactions between two genes, a driver and a target. In reality, however, most cancer synthetic lethal effects are likely complex and also polygenic, being influenced by the environment in addition to involving contributions from multiple genes. By acknowledging and delineating this complexity, we describe in this article how the success rate in cancer drug discovery and development could be improved.
MeSH term(s)	Humans ; Synthetic Lethal Mutations/genetics ; Neoplasms/drug therapy ; Neoplasms/genetics ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Drug Discovery
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2023-11-30
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-023-01557-x
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Zs.A 3613: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: First-line PARP inhibition in ovarian cancer - standard of care for all?

Banerjee, Susana N / Lord, Christopher J

Nature reviews. Clinical oncology

2019 Volume 17, Issue 3, Page(s) 136–137

MeSH term(s)	Antineoplastic Agents/therapeutic use ; BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Clinical Trials as Topic ; Female ; Humans ; Mutation ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/epidemiology ; Ovarian Neoplasms/genetics ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Progression-Free Survival ; Standard of Care
Chemical Substances	Antineoplastic Agents ; BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Poly(ADP-ribose) Polymerase Inhibitors
Language	English
Publishing date	2019-08-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2491410-1
ISSN	1759-4782 ; 1759-4774
ISSN (online)	1759-4782
ISSN	1759-4774
DOI	10.1038/s41571-020-0335-9
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Article ; Online: Dissecting PARP inhibitor resistance with functional genomics.

Pettitt, Stephen J / Lord, Christopher J

Current opinion in genetics & development

2019 Volume 54, Page(s) 55–63

Abstract: The poly-(ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib was the first licenced cancer drug that targeted an inherited form of cancer, namely ovarian cancers caused by germline BRCA1 or BRCA2 gene mutations. Multiple different PARPi have now ... ...

Abstract	The poly-(ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib was the first licenced cancer drug that targeted an inherited form of cancer, namely ovarian cancers caused by germline BRCA1 or BRCA2 gene mutations. Multiple different PARPi have now been approved for use in a wider group of gynaecological cancers as well as for the treatment of BRCA-gene mutant breast cancer. Despite these advances, resistance to PARPi is a common clinical phenotype. Understanding, at the molecular level, how tumour cells respond to PARPi has the potential to inform how these drugs should be used clinically and since the discovery of this drug class, multiple different functional genomic strategies have been employed to dissect PARPi sensitivity and resistance. These have included genetic perturbation via classical gene targeting, gene silencing by siRNA or shRNA or transposon mutagenesis techniques. Recently, CRISPR-Cas9-based mutagenesis has greatly expanded the available range of relevant preclinical models and the precision of mutagenesis. Here, we review how these approaches have been used either in low-throughput, hypothesis-testing experiments or in the setting of large, hypothesis-generating, genetic screens aimed at understanding the molecular basis of PARPi sensitivity and resistance.
MeSH term(s)	BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Drug Resistance, Neoplasm/genetics ; Female ; Germ-Line Mutation/genetics ; Humans ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Phthalazines/therapeutic use ; Piperazines/therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Poly(ADP-ribose) Polymerases/genetics
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Phthalazines ; Piperazines ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; olaparib (WOH1JD9AR8)
Language	English
Publishing date	2019-04-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1077312-5
ISSN	1879-0380 ; 0959-437X
ISSN (online)	1879-0380
ISSN	0959-437X
DOI	10.1016/j.gde.2019.03.001
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Article ; Online: Synthetic lethal therapies for cancer: what's next after PARP inhibitors?

Ashworth, Alan / Lord, Christopher J

Nature reviews. Clinical oncology

2018 Volume 15, Issue 9, Page(s) 564–576

Abstract: 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 ...

Abstract	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.
MeSH term(s)	BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Drug Resistance, Neoplasm/genetics ; Female ; Humans ; Loss of Function Mutation/genetics ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Poly(ADP-ribose) Polymerases/genetics ; Synthetic Lethal Mutations/genetics
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30)
Language	English
Publishing date	2018-06-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2491410-1
ISSN	1759-4782 ; 1759-4774
ISSN (online)	1759-4782
ISSN	1759-4774
DOI	10.1038/s41571-018-0055-6
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Zs.A 6029: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Integrative analysis of large-scale loss-of-function screens identifies robust cancer-associated genetic interactions.

Lord, Christopher J / Quinn, Niall / Ryan, Colm J

eLife

2020 Volume 9

Abstract: Genetic interactions, including synthetic lethal effects, can now be systematically identified in cancer cell lines using high-throughput genetic perturbation screens. Despite this advance, few genetic interactions have been reproduced across multiple ... ...

Abstract	Genetic interactions, including synthetic lethal effects, can now be systematically identified in cancer cell lines using high-throughput genetic perturbation screens. Despite this advance, few genetic interactions have been reproduced across multiple studies and many appear highly context-specific. Here, by developing a new computational approach, we identified 220 robust driver-gene associated genetic interactions that can be reproduced across independent experiments and across non-overlapping cell line panels. Analysis of these interactions demonstrated that: (i) oncogene addiction effects are more robust than oncogene-related synthetic lethal effects; and (ii) robust genetic interactions are enriched among gene pairs whose protein products physically interact. Exploiting the latter observation, we used a protein-protein interaction network to identify robust synthetic lethal effects associated with passenger gene alterations and validated two new synthetic lethal effects. Our results suggest that protein-protein interaction networks can be used to prioritise therapeutic targets that will be more robust to tumour heterogeneity.
MeSH term(s)	Cell Line, Tumor ; Computational Biology ; Epistasis, Genetic/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Genes, Lethal/genetics ; Humans ; Loss of Function Mutation/genetics ; Neoplasms/genetics ; Oncogenes/genetics ; Protein Interaction Maps/genetics
Language	English
Publishing date	2020-05-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.58925
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Article ; Online: Opinion: PARP inhibitors in cancer-what do we still need to know?

Wicks, Andrew J / Krastev, Dragomir B / Pettitt, Stephen J / Tutt, Andrew N J / Lord, Christopher J

Open biology

2022 Volume 12, Issue 7, Page(s) 220118

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Drug Resistance, Neoplasm/genetics ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors
Language	English
Publishing date	2022-07-27
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2630944-0
ISSN	2046-2441 ; 2046-2441
ISSN (online)	2046-2441
ISSN	2046-2441
DOI	10.1098/rsob.220118
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