Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors
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) deficien...
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| Veröffentlicht in: | Clinical cancer research 2017-02, Vol.23 (4), p.1001-1011 |
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| creator | Jdey, Wael Thierry, Sylvain Russo, Christophe Devun, Flavien Al Abo, Muthana Noguiez-Hellin, Patricia Sun, Jian-Sheng Barillot, Emmanuel Zinovyev, Andrei Kuperstein, Inna Pommier, Yves Dutreix, Marie |
| description | 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.
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.
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.
Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status.
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| doi_str_mv | 10.1158/1078-0432.CCR-16-1193 |
| format | Article |
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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.
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.
Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status.
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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.
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.
Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status.
.</description><subject>Auditory defects</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Cell survival</subject><subject>Chemical Sciences</subject><subject>Combined treatment</subject><subject>Damage accumulation</subject><subject>Damage prevention</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA End-Joining Repair - drug effects</subject><subject>DNA repair</subject><subject>Drugs</subject><subject>Experimental design</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Genetics</subject><subject>Homologous recombination</subject><subject>Homologous Recombination - genetics</subject><subject>Homology</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Lethality</subject><subject>Life Sciences</subject><subject>Multilevel</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - genetics</subject><subject>Neoplasms - pathology</subject><subject>Phthalazines - administration & dosage</subject><subject>Phthalazines - adverse effects</subject><subject>Piperazines - administration & dosage</subject><subject>Piperazines - adverse effects</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - adverse effects</subject><subject>Poly(ADP-ribose) Polymerases - genetics</subject><subject>Rad51 Recombinase - genetics</subject><subject>Repair</subject><subject>Sensitivity analysis</subject><subject>Subpopulations</subject><subject>Synthetic Lethal Mutations - drug effects</subject><subject>Tumor cell lines</subject><subject>Tumor cells</subject><subject>Tumor Suppressor p53-Binding Protein 1 - genetics</subject><subject>Tumors</subject><subject>X-ray Repair Cross Complementing Protein 1 - genetics</subject><subject>XRCC1 protein</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkcFu1DAQhiMEoqXwCCBLXBBSiseOY5tbyJa20gqqUs5WnLUbVxt7sZOiffs62rYHTpxmDt-M5p-vKN4DPgVg4gtgLkpcUXLattcl1CWApC-KY2CMl5TU7GXun5ij4k1KdxhDBbh6XRwRzpjEjB4XYRXn23IV3b3x6NfeT4OZXI_WZhq6rZv2X9G3_a5LyflbdDOPIaLWbLfo3PiFS-ivmwbUoTaM2vlucsGjYFGT3OpHgzq_QVfN9RW69IPTbgoxvS1e2W6bzLvHelL8_n52016U65_nl22zLvuKkamkusKc9YIyC0bWBmuhsWaiJ1YYou0GjDHYSiFr3nPMJDGUSwHaYmklsfSk-HzYm2OoXXRjF_cqdE5dNGs1-sErTIXEkpB7yPCnA7yL4c9s0qRGl_qcs_MmzEmB4ERUnIH4D5QtP6bAM_rxH_QuzNHn1AqkoBUhApNMsQPVx5BSNPb5WsBqMa0Wi2qxqLJpBbVaTOe5D4_bZz2azfPUk1r6ACuToaI</recordid><startdate>20170215</startdate><enddate>20170215</enddate><creator>Jdey, Wael</creator><creator>Thierry, Sylvain</creator><creator>Russo, Christophe</creator><creator>Devun, Flavien</creator><creator>Al Abo, Muthana</creator><creator>Noguiez-Hellin, Patricia</creator><creator>Sun, Jian-Sheng</creator><creator>Barillot, Emmanuel</creator><creator>Zinovyev, Andrei</creator><creator>Kuperstein, Inna</creator><creator>Pommier, Yves</creator><creator>Dutreix, Marie</creator><general>American Association for Cancer Research Inc</general><general>American Association for Cancer Research</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T5</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0003-0614-1931</orcidid></search><sort><creationdate>20170215</creationdate><title>Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors</title><author>Jdey, Wael ; Thierry, Sylvain ; Russo, Christophe ; Devun, Flavien ; Al Abo, Muthana ; Noguiez-Hellin, Patricia ; Sun, Jian-Sheng ; Barillot, Emmanuel ; Zinovyev, Andrei ; Kuperstein, Inna ; Pommier, Yves ; Dutreix, Marie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c452t-3b4075c835f1e96e0b8b0b58c2f8e2bfd1eee0f98967c70592e37981bf09f92f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Auditory defects</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Cell death</topic><topic>Cell Line, Tumor</topic><topic>Cell survival</topic><topic>Chemical Sciences</topic><topic>Combined treatment</topic><topic>Damage accumulation</topic><topic>Damage prevention</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA End-Joining Repair - drug effects</topic><topic>DNA repair</topic><topic>Drugs</topic><topic>Experimental design</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Genetics</topic><topic>Homologous recombination</topic><topic>Homologous Recombination - genetics</topic><topic>Homology</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>Lethality</topic><topic>Life Sciences</topic><topic>Multilevel</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - genetics</topic><topic>Neoplasms - pathology</topic><topic>Phthalazines - administration & dosage</topic><topic>Phthalazines - adverse effects</topic><topic>Piperazines - administration & dosage</topic><topic>Piperazines - adverse effects</topic><topic>Poly(ADP-ribose) polymerase</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors - adverse effects</topic><topic>Poly(ADP-ribose) Polymerases - genetics</topic><topic>Rad51 Recombinase - genetics</topic><topic>Repair</topic><topic>Sensitivity analysis</topic><topic>Subpopulations</topic><topic>Synthetic Lethal Mutations - drug effects</topic><topic>Tumor cell lines</topic><topic>Tumor cells</topic><topic>Tumor Suppressor p53-Binding Protein 1 - genetics</topic><topic>Tumors</topic><topic>X-ray Repair Cross Complementing Protein 1 - genetics</topic><topic>XRCC1 protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jdey, Wael</creatorcontrib><creatorcontrib>Thierry, Sylvain</creatorcontrib><creatorcontrib>Russo, Christophe</creatorcontrib><creatorcontrib>Devun, Flavien</creatorcontrib><creatorcontrib>Al Abo, Muthana</creatorcontrib><creatorcontrib>Noguiez-Hellin, Patricia</creatorcontrib><creatorcontrib>Sun, Jian-Sheng</creatorcontrib><creatorcontrib>Barillot, Emmanuel</creatorcontrib><creatorcontrib>Zinovyev, Andrei</creatorcontrib><creatorcontrib>Kuperstein, Inna</creatorcontrib><creatorcontrib>Pommier, Yves</creatorcontrib><creatorcontrib>Dutreix, Marie</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jdey, Wael</au><au>Thierry, Sylvain</au><au>Russo, Christophe</au><au>Devun, Flavien</au><au>Al Abo, Muthana</au><au>Noguiez-Hellin, Patricia</au><au>Sun, Jian-Sheng</au><au>Barillot, Emmanuel</au><au>Zinovyev, Andrei</au><au>Kuperstein, Inna</au><au>Pommier, Yves</au><au>Dutreix, Marie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2017-02-15</date><risdate>2017</risdate><volume>23</volume><issue>4</issue><spage>1001</spage><epage>1011</epage><pages>1001-1011</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>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.
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.
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.
Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status.
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| ispartof | Clinical cancer research, 2017-02, Vol.23 (4), p.1001-1011 |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Auditory defects Breast cancer Cancer Cancer therapies Cell death Cell Line, Tumor Cell survival Chemical Sciences Combined treatment Damage accumulation Damage prevention Deoxyribonucleic acid DNA DNA damage DNA End-Joining Repair - drug effects DNA repair Drugs Experimental design Gene expression Gene Expression Regulation, Neoplastic - drug effects Genetics Homologous recombination Homologous Recombination - genetics Homology Humans Inhibitors Lethality Life Sciences Multilevel Neoplasms - drug therapy Neoplasms - genetics Neoplasms - pathology Phthalazines - administration & dosage Phthalazines - adverse effects Piperazines - administration & dosage Piperazines - adverse effects Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage Poly(ADP-ribose) Polymerase Inhibitors - adverse effects Poly(ADP-ribose) Polymerases - genetics Rad51 Recombinase - genetics Repair Sensitivity analysis Subpopulations Synthetic Lethal Mutations - drug effects Tumor cell lines Tumor cells Tumor Suppressor p53-Binding Protein 1 - genetics Tumors X-ray Repair Cross Complementing Protein 1 - genetics XRCC1 protein |
| title | Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors |
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