CANCER-ASSOCIATED SF3B1 MUTATIONS CONFER A BRCA-LIKE CELLULAR PHENOTYPE AND SYNTHETIC LETHALITY TO PARP INHIBITORS

2022 ◽  
pp. canres.1843.2021
Author(s):  
Katrina M Lappin ◽  
Eliana M Barros ◽  
Satpal S Jhujh ◽  
Gareth W Irwin ◽  
Hayley McMillan ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
Cellular Phenotype

In silico discovery of novel flavonoids as poly ADP ribose polymerase (PARP) inhibitors

2020 ◽  
Vol 16 ◽  
Author(s):  
Ashish Shah ◽  
Ghanshyam Parmar ◽  
Avinash Kumar Seth
Keyword(s):  
Virtual Screening ◽  
In Silico ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Docking Studies ◽  
Docking Score ◽  
Docking Method ◽  
Anti Cancer ◽  
In Silico Toxicity

Background: The concept of synthetic lethality is emerging field in the treatment of cancer and can be applied for new drug development of cancer as it has been already represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. Objectives: In this study we performed virtual screening of 329 flavonoids obtained from Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target (NPACT) database to identify novel PARP inhibitors. Materials and methods: Virtual screening carried out using different In Silico methods which includes molecular docking studies, prediction of druglikeness and In Silico toxicity studies. Results: Fifteen out of 329 flavonoids achieved better docking score as compared to rucaparib which is an FDA approved PARP inhibitor. These 15 hits were again rescored using accurate docking mode and drug-likeliness properties were evaluated. Accuracy of docking method was checked using re-docking. Finally NPACT00183 and NPACT00280 were identified as potential PARP inhibitors with docking score of -139.237 and -129.36 respectively. These two flavonoids were also showed no AMES toxicity and no carcinogenicity which was predicted using admetSAR. Conclusion: Our finding suggests that NPACT00183 and NPACT00280 have promising potential to be further explored as PARP inhibitors.

scholarly journals Predictors and Modulators of Synthetic Lethality: An Update on PARP Inhibitors and Personalized Medicine

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Stephen Murata ◽  
Catherine Zhang ◽  
Nathan Finch ◽  
Kevin Zhang ◽  
Loredana Campo ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Advanced Ovarian Cancer ◽  
Parp Inhibitors ◽  
Damage Repair ◽  
Trial Testing ◽  
United States Food ◽  
States Food ◽  
And Personalized Medicine ◽  
Inhibitor Treatment

Poly(ADP-ribose) polymerase (PARP) inhibitors have proven to be successful agents in inducing synthetic lethality in several malignancies. Several PARP inhibitors have reached clinical trial testing for treatment in different cancers, and, recently, Olaparib (AZD2281) has gained both United States Food and Drug Administration (USFDA) and the European Commission (EC) approval for use inBRCA-mutated advanced ovarian cancer treatment. The need to identify biomarkers, their interactions in DNA damage repair pathways, and their potential utility in identifying patients who are candidates for PARP inhibitor treatment is well recognized. In this review, we detail many of the biomarkers that have been investigated for their ability to predict both PARP inhibitor sensitivity and resistance in preclinical studies as well as the results of several clinical trials that have tested the safety and efficacy of different PARP inhibitor agents inBRCAand non-BRCA-mutated cancers.

scholarly journals Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance

2017 ◽  
Author(s):  
Stephen J. Pettitt ◽  
Dragomir B. Krastev ◽  
Inger Brandsma ◽  
Amy Drean ◽  
Feifei Song ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Point Mutations ◽  
Underlying Mechanism ◽  
Parp Inhibitors ◽  
High Density ◽  
Single Amino Acid ◽  
Genome Wide ◽  
Amino Acid Mutations

AbstractPARP inhibitors (PARPi) target homologous recombination defective tumour cells via synthetic lethality. Genome-wide and high-density CRISPR-Cas9 “tag, mutate and enrich” mutagenesis screens identified single amino acid mutations in PARP1 that cause profound PARPi-resistance. These included PARP1 mutations outside of the DNA interacting regions of the protein, such as mutations in solvent exposed regions of the catalytic domain and clusters of mutations around points of contact between ZnF, WGR and HD domains. These mutations altered PARP1 trapping, as did a mutation found in a clinical case of PARPi resistance. These genetic studies reinforce the importance of trapped PARP1 as a key cytotoxic DNA lesion and suggest that interactions between non-DNA binding domains of PARP1 influence cytotoxicity. Finally, different mechanisms of PARPi resistance (BRCA1 reversion, PARP1, 53BP1, REV7 mutation) had differing effects on chemotherapy sensitivity, suggesting that the underlying mechanism of PARPi resistance likely influences the success of subsequent therapies.

scholarly journals PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2054
Author(s):  
Elizabeth K. Lee ◽  
Ursula A. Matulonis
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Parp Inhibition ◽  
Combination Therapies ◽  
Mechanisms Of Resistance ◽  
Damage Repair ◽  
Inhibitor Resistance

The use of PARP inhibitors (PARPi) is growing widely as FDA approvals have shifted its use from the recurrence setting to the frontline setting. In parallel, the population developing PARPi resistance is increasing. Here we review the role of PARP, DNA damage repair, and synthetic lethality. We discuss mechanisms of resistance to PARP inhibition and how this informs on novel combinations to re-sensitize cancer cells to PARPi.

scholarly journals Recent advancements in PARP inhibitors-based targeted cancer therapy

2020 ◽  
Vol 3 (3) ◽  
pp. 187-201
Author(s):  
Ping Zhou ◽  
Justin Wang ◽  
Daniel Mishail ◽  
Cun-Yu Wang
Keyword(s):  
Molecular Mechanisms ◽  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
Targeted Cancer Therapy ◽  
End Joining ◽  
Crucial Issue ◽  
New Class ◽  
Fda Approval ◽  
Non Homologous End Joining ◽  
Shed Light

Abstract Poly(ADP-ribose) polymerase inhibitors (PARPi) are a new class of agents with unparalleled clinical achievement for driving synthetic lethality in BRCA-deficient cancers. Recent FDA approval of PARPi has motivated clinical trials centered around the optimization of PARPi-associated therapies in a variety of BRCA-deficient cancers. This review highlights recent advancements in understanding the molecular mechanisms of PARP ‘trapping’ and synthetic lethality. Particular attention is placed on the potential extension of PARPi therapies from BRCA-deficient patients to populations with other homologous recombination-deficient backgrounds, and common characteristics of PARPi and non-homologous end-joining have been elucidated. The synergistic antitumor effect of combining PARPi with various immune checkpoint blockades has been explored to evaluate the potential of combination therapy in attaining greater therapeutic outcome. This has shed light onto the differing classifications of PARPi as well as the factors that result in altered PARPi activity. Lastly, acquired chemoresistance is a crucial issue for clinical application of PARPi. The molecular mechanisms underlying PARPi resistance and potential overcoming strategies are discussed.

scholarly journals Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Daniel R. Principe ◽  
Matthew Narbutis ◽  
Regina Koch ◽  
Ajay Rana
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
The Cancer Genome Atlas ◽  
Parp Inhibition ◽  
Repair Pathway ◽  
Wide Range ◽  
Recombination Pathway ◽  
Pan Cancer

AbstractPARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors. This approach is based on the long-standing hypothesis that PARP inhibition will impair the repair of single stranded breaks, causing synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination. While this is now well accepted and has been the basis of several successful clinical trials, emerging evidence strongly suggests that mutation to several additional genes involved in homologous recombination may also have predictive value for PARP inhibitors. While this notion is supported by early clinical evidence, the mutation frequencies of these and other functionally related genes are largely unknown, particularly in cancers not classically associated with homologous recombination deficiency. We therefore evaluated the mutation status of 22 genes associated with the homologous recombination DNA repair pathway or PARP inhibitor sensitivity, first in a pan-cancer cohort of 55,586 patients, followed by a more focused analysis in The Cancer Genome Atlas cohort of 12,153 patients. In both groups we observed high rates of mutations in a variety of HR-associated genes largely unexplored in the setting of PARP inhibition, many of which were associated also with poor clinical outcomes. We then extended our study to determine which mutations have a known oncogenic role, as well as similar to known oncogenic mutations that may have a similar phenotype. Finally, we explored the individual cancer histologies in which these genomic alterations are most frequent. We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.

Drugs driven synthetic lethality: getting rid of tumor genetics with combination of Dbait and PARP inhibitors

2016 ◽  
Vol 61 ◽  
pp. S115
Author(s):  
M. Dutreix ◽  
W. Jdey ◽  
S. Thierry ◽  
F. Devun ◽  
I. Kuperstein ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
Tumor Genetics

ARID1A: A new synthetic lethality partner to PARP inhibitors in the treatment of ovarian clear cell cancer

2019 ◽  
Vol 154 ◽  
pp. 78
Author(s):  
V.A. Yakovlev ◽  
S.A. Sullivan ◽  
L.A. Rubinsak ◽  
E.C. Fields ◽  
S.M. Temkin
Keyword(s):  
Clear Cell ◽  
Synthetic Lethality ◽  
Cell Cancer ◽  
Parp Inhibitors
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