Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors
Inhibition of PARP is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical PARP inhibitor (PARPi) olaparib through activation of the P-...
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| Veröffentlicht in: | Cancer discovery 2013-01, Vol.3 (1), p.68-81 |
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| creator | Jaspers, Janneke E Kersbergen, Ariena Boon, Ute Sol, Wendy van Deemter, Liesbeth Zander, Serge A Drost, Rinske Wientjens, Ellen Ji, Jiuping Aly, Amal Doroshow, James H Cranston, Aaron Martin, Niall M B Lau, Alan O'Connor, Mark J Ganesan, Shridar Borst, Piet Jonkers, Jos Rottenberg, Sven |
| description | Inhibition of PARP is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical PARP inhibitor (PARPi) olaparib through activation of the P-glycoprotein drug efflux transporter. Here, we show that tumor-specific genetic inactivation of P-glycoprotein increases the long-term response of BRCA1-deficient mouse mammary tumors to olaparib, but these tumors eventually developed PARPi resistance. In a fraction of cases, this resistance is caused by partial restoration of homologous recombination due to somatic loss of 53BP1. Importantly, PARPi resistance was minimized by long-term treatment with the novel PARP inhibitor AZD2461, which is a poor P-glycoprotein substrate. Together, our data suggest that restoration of homologous recombination is an important mechanism for PARPi resistance in BRCA1-deficient mammary tumors and that the risk of relapse of BRCA1-deficient tumors can be effectively minimized by using optimized PARP inhibitors.
In this study, we show that loss of 53BP1 causes resistance to PARP inhibition in mouse mammary tumors that are deficient in BRCA1. We hypothesize that low expression or absence of 53BP1 also reduces the response of patients with BRCA1-deficient tumors to PARP inhibitors. |
| doi_str_mv | 10.1158/2159-8290.CD-12-0049 |
| format | Article |
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In this study, we show that loss of 53BP1 causes resistance to PARP inhibition in mouse mammary tumors that are deficient in BRCA1. We hypothesize that low expression or absence of 53BP1 also reduces the response of patients with BRCA1-deficient tumors to PARP inhibitors.</description><identifier>ISSN: 2159-8274</identifier><identifier>EISSN: 2159-8290</identifier><identifier>DOI: 10.1158/2159-8290.CD-12-0049</identifier><identifier>PMID: 23103855</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Antineoplastic Agents - therapeutic use ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - deficiency ; BRCA1 Protein - genetics ; Cell Line, Tumor ; Chromosomal Proteins, Non-Histone - genetics ; DNA Damage ; DNA-Binding Proteins - genetics ; Drug Resistance, Neoplasm ; Enzyme Inhibitors - therapeutic use ; Female ; Mammary Neoplasms, Animal - drug therapy ; Mice ; Mutation ; Phthalazines - therapeutic use ; Piperazines - therapeutic use ; Piperidines - therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors ; Tumor Suppressor p53-Binding Protein 1</subject><ispartof>Cancer discovery, 2013-01, Vol.3 (1), p.68-81</ispartof><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c576t-35f4aef7050398c74e8a886a89f29d99d9171a8429620df1e2ad78e69dc194b3</citedby><cites>FETCH-LOGICAL-c576t-35f4aef7050398c74e8a886a89f29d99d9171a8429620df1e2ad78e69dc194b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23103855$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jaspers, Janneke E</creatorcontrib><creatorcontrib>Kersbergen, Ariena</creatorcontrib><creatorcontrib>Boon, Ute</creatorcontrib><creatorcontrib>Sol, Wendy</creatorcontrib><creatorcontrib>van Deemter, Liesbeth</creatorcontrib><creatorcontrib>Zander, Serge A</creatorcontrib><creatorcontrib>Drost, Rinske</creatorcontrib><creatorcontrib>Wientjens, Ellen</creatorcontrib><creatorcontrib>Ji, Jiuping</creatorcontrib><creatorcontrib>Aly, Amal</creatorcontrib><creatorcontrib>Doroshow, James H</creatorcontrib><creatorcontrib>Cranston, Aaron</creatorcontrib><creatorcontrib>Martin, Niall M B</creatorcontrib><creatorcontrib>Lau, Alan</creatorcontrib><creatorcontrib>O'Connor, Mark J</creatorcontrib><creatorcontrib>Ganesan, Shridar</creatorcontrib><creatorcontrib>Borst, Piet</creatorcontrib><creatorcontrib>Jonkers, Jos</creatorcontrib><creatorcontrib>Rottenberg, Sven</creatorcontrib><title>Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors</title><title>Cancer discovery</title><addtitle>Cancer Discov</addtitle><description>Inhibition of PARP is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical PARP inhibitor (PARPi) olaparib through activation of the P-glycoprotein drug efflux transporter. Here, we show that tumor-specific genetic inactivation of P-glycoprotein increases the long-term response of BRCA1-deficient mouse mammary tumors to olaparib, but these tumors eventually developed PARPi resistance. In a fraction of cases, this resistance is caused by partial restoration of homologous recombination due to somatic loss of 53BP1. Importantly, PARPi resistance was minimized by long-term treatment with the novel PARP inhibitor AZD2461, which is a poor P-glycoprotein substrate. Together, our data suggest that restoration of homologous recombination is an important mechanism for PARPi resistance in BRCA1-deficient mammary tumors and that the risk of relapse of BRCA1-deficient tumors can be effectively minimized by using optimized PARP inhibitors.
In this study, we show that loss of 53BP1 causes resistance to PARP inhibition in mouse mammary tumors that are deficient in BRCA1. We hypothesize that low expression or absence of 53BP1 also reduces the response of patients with BRCA1-deficient tumors to PARP inhibitors.</description><subject>Animals</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 1 - deficiency</subject><subject>BRCA1 Protein - genetics</subject><subject>Cell Line, Tumor</subject><subject>Chromosomal Proteins, Non-Histone - genetics</subject><subject>DNA Damage</subject><subject>DNA-Binding Proteins - genetics</subject><subject>Drug Resistance, Neoplasm</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Female</subject><subject>Mammary Neoplasms, Animal - drug therapy</subject><subject>Mice</subject><subject>Mutation</subject><subject>Phthalazines - therapeutic use</subject><subject>Piperazines - therapeutic use</subject><subject>Piperidines - therapeutic use</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors</subject><subject>Tumor Suppressor p53-Binding Protein 1</subject><issn>2159-8274</issn><issn>2159-8290</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUdtKAzEUDKLYUvsHInn0ZWuum-RF6MUbFCzS95Bms3ZlLzXZFfx7s7QuCoGEycycc-YAcI3RDGMu7wjmKpFEodlylWCSIMTUGRgP8PnwFmwEpiF8INRzGEfiEowIxYhKzsdgu25CgE0OOV1sMLSmCy7AzfxtA4t6X-yKtvHQu1CE1tTWRRAuvDU4qbrWtC6DVRMVsDJVZfw3bLuq8eEKXOSmDG56uidg-_iwXT4n69enl-V8nVgu0jahPGfG5QJxRJW0gjlppEyNVDlRmYoHC2wkIyolKMuxIyYT0qUqs1ixHZ2A-6PtodtVLrOubr0p9cEXfS-6MYX-_1MXe_3efGnBscSIR4Pbk4FvPjsXWl0VwbqyNLWLY2lMBOUcqVRGKjtSrY-BeZcPZTDS_Up0n7fus9fLVVTqPu4ou_nb4iD6XQD9ATrShug</recordid><startdate>20130101</startdate><enddate>20130101</enddate><creator>Jaspers, Janneke E</creator><creator>Kersbergen, Ariena</creator><creator>Boon, Ute</creator><creator>Sol, Wendy</creator><creator>van Deemter, Liesbeth</creator><creator>Zander, Serge A</creator><creator>Drost, Rinske</creator><creator>Wientjens, Ellen</creator><creator>Ji, Jiuping</creator><creator>Aly, Amal</creator><creator>Doroshow, James H</creator><creator>Cranston, Aaron</creator><creator>Martin, Niall M B</creator><creator>Lau, Alan</creator><creator>O'Connor, Mark J</creator><creator>Ganesan, Shridar</creator><creator>Borst, Piet</creator><creator>Jonkers, Jos</creator><creator>Rottenberg, Sven</creator><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130101</creationdate><title>Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors</title><author>Jaspers, Janneke E ; 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In this study, we show that loss of 53BP1 causes resistance to PARP inhibition in mouse mammary tumors that are deficient in BRCA1. We hypothesize that low expression or absence of 53BP1 also reduces the response of patients with BRCA1-deficient tumors to PARP inhibitors.</abstract><cop>United States</cop><pmid>23103855</pmid><doi>10.1158/2159-8290.CD-12-0049</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Antineoplastic Agents - therapeutic use ATP Binding Cassette Transporter, Subfamily B, Member 1 - deficiency BRCA1 Protein - genetics Cell Line, Tumor Chromosomal Proteins, Non-Histone - genetics DNA Damage DNA-Binding Proteins - genetics Drug Resistance, Neoplasm Enzyme Inhibitors - therapeutic use Female Mammary Neoplasms, Animal - drug therapy Mice Mutation Phthalazines - therapeutic use Piperazines - therapeutic use Piperidines - therapeutic use Poly(ADP-ribose) Polymerase Inhibitors Tumor Suppressor p53-Binding Protein 1 |
| title | Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors |
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