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Ref Type Journal Article
PMID (27559053)
Authors Jdey W, Thierry S, Russo C, Devun F, Al Abo M, Noguiez-Hellin P, Sun JS, Barillot E, Zinovyev A, Kuperstein I, Pommier Y, Dutreix M
Title Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 4
Date 2017 Feb 15
URL
Abstract Text Purpose: Cancer treatments using tumor defects in DNA repair pathways have shown promising results but are restricted to small subpopulations of patients. The most advanced drugs in this field are PARP inhibitors (PARPi), which trigger synthetic lethality in tumors with homologous recombination (HR) deficiency. Using AsiDNA, an inhibitor of HR and nonhomologous end joining, together with PARPi should allow bypassing the genetic restriction for PARPi efficacy.Experimental Design: We characterized the DNA repair inhibition activity of PARPi (olaparib) and AsiDNA by monitoring repair foci formation and DNA damage. We analyzed the cell survival to standalone and combined treatments of 21 tumor cells and three nontumor cells. In 12 breast cancer (BC) cell lines, correlation with sensitivity to each drug and transcriptome were statistically analyzed to identify resistance pathways.Results: Molecular analyses demonstrate that olaparib and AsiDNA respectively prevent recruitment of XRCC1 and RAD51/53BP1 repair enzymes to damage sites. Combination of both drugs increases the accumulation of unrepaired damage resulting in an increase of cell death in all tumor cells. In contrast, nontumor cells do not show an increase of DNA damage nor lethality. Analysis of multilevel omics data from BC cells highlighted different DNA repair and cell-cycle molecular profiles associated with resistance to AsiDNA or olaparib, rationalizing combined treatment. Treatment synergy was also confirmed with six other PARPi in development.Conclusions: Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status. Clin Cancer Res; 23(4); 1001-11. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
AsiDNA AsiDNA is an oligodeoxyribonucleotide drug that acts as a DNA repair pathway antagonist by mimicking double-stranded DNA breaks and subsequently recruiting DNA repair proteins, thereby preventing the repair of other DNA damaged sites, and thus, potentially leading to increased cell death and inhibition of cell proliferation (PMID: 27559053).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown melanoma not applicable AsiDNA Preclinical - Cell culture Actionable In a preclinical study, AsiDNA inhibited survival of melanoma cell lines in culture (PMID: 27559053). 27559053
Unknown unknown breast cancer not applicable AsiDNA + Olaparib Preclinical - Cell culture Actionable In a preclinical study, AsiDNA treatment resulted in increased sensitivity to Lynparza (olaparib), inhibiting DNA repair and cell proliferation, and inducing death in breast cancer cell lines in culture (PMID: 27559053). 27559053
Unknown unknown head and neck cancer not applicable AsiDNA Preclinical - Cell culture Actionable In a preclinical study, AsiDNA inhibited survival of a head and neck cancer cell line in culture (PMID: 27559053). 27559053
Unknown unknown breast cancer not applicable AsiDNA Preclinical - Cell culture Actionable In a preclinical study, AsiDNA inhibited DNA repair and proliferation, and induced death in breast cancer cell lines in culture (PMID: 27559053). 27559053
Unknown unknown melanoma not applicable AsiDNA + Olaparib Preclinical - Cell culture Actionable In a preclinical study, AsiDNA treatment led to increased sensitivity to Lynparza (olaparib), resulting in decreased survival of melanoma cell lines in culture (PMID: 27559053). 27559053
Unknown unknown breast cancer not applicable AsiDNA + Talazoparib Preclinical - Cell culture Actionable In a preclinical study, AsiDNA and Talzenna (talazoparib) combination treatment resulted in increased cell death and inhibition of proliferation in breast cancer cell lines compared to Talzenna (talazoparib) alone in culture (PMID: 27559053). 27559053
Unknown unknown glioblastoma multiforme not applicable AsiDNA Preclinical - Cell culture Actionable In a preclinical study, AsiDNA inhibited survival of glioblastoma cell lines in culture (PMID: 27559053). 27559053
Unknown unknown hematologic cancer not applicable AsiDNA Preclinical - Cell culture Actionable In a preclinical study, AsiDNA inhibited survival of hematologic cancer cell lines in culture (PMID: 27559053). 27559053
Unknown unknown breast cancer not applicable AsiDNA + Iniparib Preclinical - Cell culture Actionable In a preclinical study, AsiDNA and Iniparib combination treatment resulted in increased cell death and inhibition of proliferation in breast cancer cell lines compared to Iniparib alone in culture (PMID: 27559053). 27559053
Unknown unknown head and neck cancer not applicable AsiDNA + Olaparib Preclinical - Cell culture Actionable In a preclinical study, AsiDNA treatment led to increased sensitivity to Lynparza (olaparib), resulting in decreased survival of a head and neck cancer cell line in culture (PMID: 27559053). 27559053
Unknown unknown breast cancer not applicable AsiDNA + AZD2461 Preclinical - Cell culture Actionable In a preclinical study, AsiDNA and AZD2461 combination treatment resulted in increased cell death and inhibition of proliferation in breast cancer cell lines compared to AZD2461 alone in culture (PMID: 27559053). 27559053
Unknown unknown breast cancer not applicable AsiDNA + Rucaparib Preclinical - Cell culture Actionable In a preclinical study, AsiDNA and Rubraca (rucaparib) combination treatment resulted in increased cell death and inhibition of proliferation in breast cancer cell lines compared to Rubraca (rucaparib) alone in culture (PMID: 27559053). 27559053
Unknown unknown breast cancer not applicable AsiDNA + Niraparib Preclinical - Cell culture Actionable In a preclinical study, AsiDNA and Zejula (niraparib) combination treatment resulted in increased cell death and inhibition of proliferation in breast cancer cell lines compared to Zejula (niraparib) alone in culture (PMID: 27559053). 27559053
Unknown unknown hematologic cancer not applicable AsiDNA + Olaparib Preclinical - Cell culture Actionable In a preclinical study, AsiDNA treatment sensitized hematologic cancer cell lines to Lynparza (olaparib), inhibiting survival in culture (PMID: 27559053). 27559053
Unknown unknown colon cancer not applicable AsiDNA Preclinical - Cell culture Actionable In a preclinical study, AsiDNA inhibited survival of colon cancer cell lines in culture (PMID: 27559053). 27559053
Unknown unknown cervical cancer not applicable AsiDNA + Olaparib Preclinical - Cell culture Actionable In a preclinical study, AsiDNA treatment led to increased sensitivity to Lynparza (olaparib), resulting in decreased survival in a cervical cancer cell line in culture (PMID: 27559053). 27559053
Unknown unknown glioblastoma multiforme not applicable AsiDNA + Olaparib Preclinical - Cell culture Actionable In a preclinical study, AsiDNA treatment led to increased sensitivity to Lynparza (olaparib), resulting in decreased survival of glioblastoma cell lines in culture (PMID: 27559053). 27559053
Unknown unknown colon cancer not applicable AsiDNA + Olaparib Preclinical - Cell culture Actionable In a preclinical study, AsiDNA treatment led to increased sensitivity to Lynparza (olaparib), resulting in decreased survival in colon cancer cell lines in culture (PMID: 27559053). 27559053
Unknown unknown breast cancer not applicable AsiDNA + Veliparib Preclinical - Cell culture Actionable In a preclinical study, AsiDNA and Veliparib (ABT-888) combination treatment resulted in increased cell death and inhibition of proliferation in breast cancer cell lines compared to Veliparib (ABT-888) alone in culture (PMID: 27559053). 27559053
Unknown unknown cervical cancer not applicable AsiDNA Preclinical - Cell culture Actionable In a preclinical study, AsiDNA inhibited survival of cervical cancer cell lines in culture (PMID: 27559053). 27559053