ArticleOncotarget2016
PARP1 inhibitor olaparib (Lynparza) exerts synthetic lethal effect against ligase 4-deficient melanomas.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 37 citations in OpenAlex.
- Synthetic rescue in Saccharomyces cerevisiae: Concepts, large-scale genetic mapping, and functional implications.Journal of microbiology (Seoul, Korea) · 2026Review
- Star wars against leukemia: attacking the clones.Leukemia · 2024Review
- Polθ Inhibitor (ART558) Demonstrates a Synthetic Lethal Effect with PARP and RAD52 Inhibitors in Glioblastoma Cells.International journal of molecular sciences · 2024Article
- Mammalian DNA ligases; roles in maintaining genome integrity.Journal of molecular biology · 2024Review
- Patient-derived bladder cancer organoid model to predict sensitivity and feasibility of tailored precision therapy.Current urology · 2023Article
- Class I HDAC Inhibition Leads to a Downregulation of FANCD2 and RAD51, and the Eradication of Glioblastoma Cells.Journal of personalized medicine · 2023Article
- Article
- Review
- Synthetic Lethality Targeting Polθ.Genes · 2022Review
- Targeting cell cycle regulation via the G2-M checkpoint for synthetic lethality in melanoma.Cell cycle (Georgetown, Tex.) · 2021Review
- DROSHA is recruited to DNA damage sites by the MRN complex to promote non-homologous end joining.Journal of cell science · 2021Article
- PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors.International journal of molecular sciences · 2020Article
- PS4DR: a multimodal workflow for identification and prioritization of drugs based on pathway signatures.BMC bioinformatics · 2020Article
- Epigenetic based synthetic lethal strategies in human cancers.Biomarker research · 2020Review
- Sam68 is required for the growth and survival of nonmelanoma skin cancer.Cancer medicine · 2019Article
- Prexasertib treatment induces homologous recombination deficiency and synergizes with olaparib in triple-negative breast cancer cells.Breast cancer research : BCR · 2019Article
- Eradication of LIG4-deficient glioblastoma cells by the combination of PARP inhibitor and alkylating agent.Oncotarget · 2018Article
- Rhaponticum carthamoides transformed root extract inhibits human glioma cells viability, induces double strand DNA damage, H2A.X phosphorylation, and PARP1 cleavage.Cytotechnology · 2018Article
- The Extract of Leonurus sibiricus Transgenic Roots with AtPAP1 Transcriptional Factor Induces Apoptosis via DNA Damage and Down Regulation of Selected Epigenetic Factors in Human Cancer Cells.Neurochemical research · 2018Article
- The synthetic lethal killing of RAD54B-deficient colorectal cancer cells by PARP1 inhibition is enhanced with SOD1 inhibition.Oncotarget · 2016Article
Corrections and comments
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Authors and funding
13 authors at 6 institutions in 3 countries.
Funding
Abstract
Cancer including melanoma may be ''addicted" to double strand break (DSB) repair and targeting this process could sensitize them to the lethal effect of DNA damage. PARP1 exerts an important impact on DSB repair as it binds to both single- and double- strand breaks. PARP1 inhibitors might be highly effective drugs triggering synthetic lethality in patients whose tumors have germline or somatic defects in DNA repair genes. We hypothesized that PARP1-dependent synthetic lethality could be induced in melanoma cells displaying downregulation of DSB repair genes. We observed that PARP1 inhibitor olaparib sensitized melanomas with reduced expression of DNA ligase 4 (LIG4) to an alkylatimg agent dacarbazine (DTIC) treatment in vitro, while normal melanocytes remained intact. PARP1 inhibition caused accumulation of DSBs, which was associated with apoptosis in LIG4 deficient melanoma cells. Our hypothesis that olaparib is synthetic lethal with LIG4 deficiency in melanoma cells was supported by selective anti-tumor effects of olaparib used either alone or in combination with dacarbazine (DTIC) in LIG4 deficient, but not LIG4 proficient cells. In addition, olaparib combined with DTIC inhibited the growth of LIG4 deficient human melanoma xenografts. This work for the first time demonstrates the effectiveness of a combination of PARP1 inhibitor olaparib and alkylating agent DTIC for treating LIG4 deficient melanomas. In addition, analysis of the TCGA and transcriptome microarray databases revealed numerous individual melanoma samples potentially displaying specific defects in DSB repair pathways, which may predispose them to synthetic lethality triggered by PARP1 inhibitor combined with a cytotoxic drug.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.