New Targeted Agents in Gynecologic Cancers: Synthetic Lethality, Homologous Recombination Deficiency, and PARP Inhibitors

Liu, Fong W.; Tewari, Krishnansu S.

doi:10.1007/s11864-015-0378-9

Cited by 33 publications

(28 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inhibition of PARP1 in these cancer cells is catastrophic and results in their death. This is the concept of synthetic lethality [58] and has been proposed as a potential Achilles heel in a cancer cell’s defense. Although this concept may enable the clinician to increase the therapeutic index between cancer and normal cells, it is expected that these approaches will also have the potential to develop resistance.…”

Section: Mechanisms Of Resistancementioning

confidence: 99%

Molecular chess? Hallmarks of anti-cancer drug resistance

2017

View full text Add to dashboard Cite

BackgroundThe development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years.ReviewResistance to anti-cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as (1) alteration of drug targets, (2) expression of drug pumps, (3) expression of detoxification mechanisms, (4) reduced susceptibility to apoptosis, (5) increased ability to repair DNA damage, and (6) altered proliferation. It is clear, however, that changes in stroma and tumour microenvironment, and local immunity can also contribute to the development of resistance. Cancer cells can and do use several of these mechanisms at one time, and there is considerable heterogeneity between tumours, necessitating an individualised approach to cancer treatment. As tumours are heterogeneous, positive selection of a drug-resistant population could help drive resistance, although acquired resistance cannot simply be viewed as overgrowth of a resistant cancer cell population. The development of such resistance mechanisms can be predicted from pre-existing genomic and proteomic profiles, and there are increasingly sophisticated methods to measure and then tackle these mechanisms in patients.ConclusionThe oncologist is now required to be at least one step ahead of the cancer, a process that can be likened to ‘molecular chess’. Thus, as well as an increasing role for predictive biomarkers to clinically stratify patients, it is becoming clear that personalised strategies are required to obtain best results.

show abstract

Section: Mechanisms Of Resistancementioning

confidence: 99%

Molecular chess? Hallmarks of anti-cancer drug resistance

2017

View full text Add to dashboard Cite

show abstract

“…The synthetic lethality strategy to identify novel partners for potential genetic mutations has emerged to overcome this challenge (5,8). Homologous recombination deficiency including BRCA1/2 or p53 mutations combined with an increase in replication stress may result in a tumor being more susceptible to PARP inhibition (38,45,49,56). Since these particular genes are rarely observed to be mutated in CCC, there is considerable interest in identifying alternative therapeutic options of PARP inhibitor sensitivity (2).…”

Section: Discussionmentioning

confidence: 99%

“…A high number of DNA double-strand breaks are repaired by BRCA-dependent homologous recombination (37). PARP1 may serve as an alternative or a backup pair (38). Preclinical studies revealed that proteins involved in DNA repair and response to damage, including BRCA1/2, X-ray repair cross complementing (XRCC)1, XRCC2, XRCC3, ATM serine/threonine kinase (ATM), ATR serine/threonine kinase (ATR), Chk1, Chk2, proliferating cell nuclear antigen, RAD51, MRE11 homolog, double strand break repair nuclease, ERCC excision repair 1, endonuclease non-catalytic subunit, p53, cyclin dependent kinase 12 (CDK12) and PTEN, in addition to the Fanconi anemia pathway, induce synthetic lethality with PARP inhibitors and are implicated as potential predictive markers for tumor cell response to PARP inhibitors (8,33).…”

Section: Category 1: Components Of a Backup Or A Parallel Pathway Witmentioning

confidence: 99%

Conceptual frameworks of synthetic lethality in clear cell carcinoma of the ovary (Review)

et al. 2018

View full text Add to dashboard Cite

Abstract. Targeting non-oncogenes may result in the selective death of cancer cells. Clear cell carcinoma of the ovary (CCC) may exhibit resistance against conventional chemotherapy and is associated with poor prognosis. The aim of the present report was to review synthetic lethality-based therapies for CCC. Previous English-language studies were reviewed to accumulate preclinical and clinical data on targeting synthetic lethal partners. Synthetic lethal interactions have a variety of types, involving components of a backup or parallel pathway with overlapping functions, components encoded by paralogous pairs, subunit components that form heteromeric complexes and components that are arranged in a single linear pathway. A set of candidate gene targets potentially resulting in synthetic lethality have been previously identified. HNF class homeobox, AT-rich interaction domain 1A, ATR serine/threonine kinase, ATM serine/threonine kinase, checkpoint kinase 1 and phosphatase and tensin homolog may be the key partner genes. A variety of loss of function genes in CCC are driver or passenger events and may function as synthetic lethal pairs under replication stress conditions. Further clinical studies will be required to investigate the safety and therapeutic effect of synthetic lethality pairs in CCC tumor types with replication stress.

show abstract

“…More worrisome is the 2% rate of myelodysplasia and acute myeloid leukemia seen in olaparib-treated patients (182,183). However, these are known risks of chemotherapeutics used in ovarian cancer, and it is possible that these adverse events were not due to olaparib but rather to prior chemotherapy.…”

Section: Clinical Effectiveness Of Targeting Dna Repairmentioning

confidence: 99%

Drugging the Cancers Addicted to DNA Repair

Nickoloff

Jones

Lee

et al. 2017

JNCI: Journal of the National Cancer Institute

139

114

View full text Add to dashboard Cite

Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects.

show abstract

New Targeted Agents in Gynecologic Cancers: Synthetic Lethality, Homologous Recombination Deficiency, and PARP Inhibitors

Cited by 33 publications

References 72 publications

Molecular chess? Hallmarks of anti-cancer drug resistance

Molecular chess? Hallmarks of anti-cancer drug resistance

Conceptual frameworks of synthetic lethality in clear cell carcinoma of the ovary (Review)

Drugging the Cancers Addicted to DNA Repair

Contact Info

Product

Resources

About