Chlorambucil targets BRCA1/2‐deficient tumours and counteracts PARP inhibitor resistance
Abstract Due to compromised homologous recombination (HR) repair, BRCA1‐ and BRCA2‐mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically BRCA2‐deficient cells, we screened a chemical library containing compounds i...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2019-07-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201809982 |
| _version_ | 1797282965365981184 |
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| author | Eliana MC Tacconi Sophie Badie Giuliana De Gregoriis Timo Reisländer Xianning Lai Manuela Porru Cecilia Folio John Moore Arnaud Kopp Júlia Baguña Torres Deborah Sneddon Marcus Green Simon Dedic Jonathan W Lee Ankita Sati Batra Oscar M Rueda Alejandra Bruna Carlo Leonetti Carlos Caldas Bart Cornelissen Laurent Brino Anderson Ryan Annamaria Biroccio Madalena Tarsounas |
| author_facet | Eliana MC Tacconi Sophie Badie Giuliana De Gregoriis Timo Reisländer Xianning Lai Manuela Porru Cecilia Folio John Moore Arnaud Kopp Júlia Baguña Torres Deborah Sneddon Marcus Green Simon Dedic Jonathan W Lee Ankita Sati Batra Oscar M Rueda Alejandra Bruna Carlo Leonetti Carlos Caldas Bart Cornelissen Laurent Brino Anderson Ryan Annamaria Biroccio Madalena Tarsounas |
| author_sort | Eliana MC Tacconi |
| collection | DOAJ |
| description | Abstract Due to compromised homologous recombination (HR) repair, BRCA1‐ and BRCA2‐mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically BRCA2‐deficient cells, we screened a chemical library containing compounds in clinical use. The top hit was chlorambucil, a bifunctional alkylating agent used for the treatment of chronic lymphocytic leukaemia (CLL). We establish that chlorambucil is specifically toxic to BRCA1/2‐deficient cells, including olaparib‐resistant and cisplatin‐resistant ones, suggesting the potential clinical use of chlorambucil against disease which has become resistant to these drugs. Additionally, chlorambucil eradicates BRCA2‐deficient xenografts and inhibits growth of olaparib‐resistant patient‐derived tumour xenografts (PDTXs). We demonstrate that chlorambucil inflicts replication‐associated DNA double‐strand breaks (DSBs), similarly to cisplatin, and we identify ATR, FANCD2 and the SNM1A nuclease as determinants of sensitivity to both drugs. Importantly, chlorambucil is substantially less toxic to normal cells and tissues in vitro and in vivo relative to cisplatin. Because chlorambucil and cisplatin are equally effective inhibitors of BRCA2‐compromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCA‐deficient tumours. |
| first_indexed | 2024-03-07T17:22:06Z |
| format | Article |
| id | doaj.art-60b26d5b1f0d4fb1965e8459d8be9b33 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:22:06Z |
| publishDate | 2019-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-60b26d5b1f0d4fb1965e8459d8be9b332024-03-02T19:45:09ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-07-01117n/an/a10.15252/emmm.201809982Chlorambucil targets BRCA1/2‐deficient tumours and counteracts PARP inhibitor resistanceEliana MC Tacconi0Sophie Badie1Giuliana De Gregoriis2Timo Reisländer3Xianning Lai4Manuela Porru5Cecilia Folio6John Moore7Arnaud Kopp8Júlia Baguña Torres9Deborah Sneddon10Marcus Green11Simon Dedic12Jonathan W Lee13Ankita Sati Batra14Oscar M Rueda15Alejandra Bruna16Carlo Leonetti17Carlos Caldas18Bart Cornelissen19Laurent Brino20Anderson Ryan21Annamaria Biroccio22Madalena Tarsounas23Genome Stability and Tumorigenesis Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKGenome Stability and Tumorigenesis Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKGenome Stability and Tumorigenesis Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKGenome Stability and Tumorigenesis Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKGenome Stability and Tumorigenesis Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKArea of Translational Research IRCCS Regina Elena National Cancer Institute Rome ItalyGenome Stability and Tumorigenesis Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKLung Cancer Translational Science Research Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKInstitut de Génétique et de Biologie Cellulaire et Moléculaire (IGBMC) Inserm U1258, CNRS (UMR 7104) Université de Strasbourg Illkirch FranceRadiopharmaceuticals and Molecular Imaging Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKRadiopharmaceuticals and Molecular Imaging Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKLung Cancer Translational Science Research Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKGenome Stability and Tumorigenesis Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKGenome Stability and Tumorigenesis Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKDepartment of Oncology Cancer Research UK Cambridge Institute University of Cambridge Cambridge UKDepartment of Oncology Cancer Research UK Cambridge Institute University of Cambridge Cambridge UKDepartment of Oncology Cancer Research UK Cambridge Institute University of Cambridge Cambridge UKArea of Translational Research IRCCS Regina Elena National Cancer Institute Rome ItalyDepartment of Oncology Cancer Research UK Cambridge Institute University of Cambridge Cambridge UKRadiopharmaceuticals and Molecular Imaging Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKInstitut de Génétique et de Biologie Cellulaire et Moléculaire (IGBMC) Inserm U1258, CNRS (UMR 7104) Université de Strasbourg Illkirch FranceLung Cancer Translational Science Research Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKArea of Translational Research IRCCS Regina Elena National Cancer Institute Rome ItalyGenome Stability and Tumorigenesis Group Department of Oncology The CR‐UK/MRC Oxford Institute for Radiation Oncology University of Oxford Oxford UKAbstract Due to compromised homologous recombination (HR) repair, BRCA1‐ and BRCA2‐mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically BRCA2‐deficient cells, we screened a chemical library containing compounds in clinical use. The top hit was chlorambucil, a bifunctional alkylating agent used for the treatment of chronic lymphocytic leukaemia (CLL). We establish that chlorambucil is specifically toxic to BRCA1/2‐deficient cells, including olaparib‐resistant and cisplatin‐resistant ones, suggesting the potential clinical use of chlorambucil against disease which has become resistant to these drugs. Additionally, chlorambucil eradicates BRCA2‐deficient xenografts and inhibits growth of olaparib‐resistant patient‐derived tumour xenografts (PDTXs). We demonstrate that chlorambucil inflicts replication‐associated DNA double‐strand breaks (DSBs), similarly to cisplatin, and we identify ATR, FANCD2 and the SNM1A nuclease as determinants of sensitivity to both drugs. Importantly, chlorambucil is substantially less toxic to normal cells and tissues in vitro and in vivo relative to cisplatin. Because chlorambucil and cisplatin are equally effective inhibitors of BRCA2‐compromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCA‐deficient tumours.https://doi.org/10.15252/emmm.201809982alkylating agentsBRCA1BRCA2cisplatinDNA damage responses |
| spellingShingle | Eliana MC Tacconi Sophie Badie Giuliana De Gregoriis Timo Reisländer Xianning Lai Manuela Porru Cecilia Folio John Moore Arnaud Kopp Júlia Baguña Torres Deborah Sneddon Marcus Green Simon Dedic Jonathan W Lee Ankita Sati Batra Oscar M Rueda Alejandra Bruna Carlo Leonetti Carlos Caldas Bart Cornelissen Laurent Brino Anderson Ryan Annamaria Biroccio Madalena Tarsounas Chlorambucil targets BRCA1/2‐deficient tumours and counteracts PARP inhibitor resistance EMBO Molecular Medicine alkylating agents BRCA1 BRCA2 cisplatin DNA damage responses |
| title | Chlorambucil targets BRCA1/2‐deficient tumours and counteracts PARP inhibitor resistance |
| title_full | Chlorambucil targets BRCA1/2‐deficient tumours and counteracts PARP inhibitor resistance |
| title_fullStr | Chlorambucil targets BRCA1/2‐deficient tumours and counteracts PARP inhibitor resistance |
| title_full_unstemmed | Chlorambucil targets BRCA1/2‐deficient tumours and counteracts PARP inhibitor resistance |
| title_short | Chlorambucil targets BRCA1/2‐deficient tumours and counteracts PARP inhibitor resistance |
| title_sort | chlorambucil targets brca1 2 deficient tumours and counteracts parp inhibitor resistance |
| topic | alkylating agents BRCA1 BRCA2 cisplatin DNA damage responses |
| url | https://doi.org/10.15252/emmm.201809982 |
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