Chlorambucil targets BRCA1/2‐deficient tumours and counteracts PARP inhibitor resistance
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 clinica...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
EMBO Press
2019
|
| _version_ | 1797081070716321792 |
|---|---|
| author | Tacconi, E Badie, S De Gregoriis, G Reisländer, T Lai, X Porru, M Folio, C Moore, J Kopp, A Baguña Torres, J Sneddon, D Green, M Dedic, S Lee, J Batra, A Rueda, O Bruna, A Leonetti, C Caldas, C Cornelissen, B Brino, L Ryan, A Biroccio, A Tarsounas, M |
| author_facet | Tacconi, E Badie, S De Gregoriis, G Reisländer, T Lai, X Porru, M Folio, C Moore, J Kopp, A Baguña Torres, J Sneddon, D Green, M Dedic, S Lee, J Batra, A Rueda, O Bruna, A Leonetti, C Caldas, C Cornelissen, B Brino, L Ryan, A Biroccio, A Tarsounas, M |
| author_sort | Tacconi, E |
| collection | OXFORD |
| description | 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 | 2024-03-07T01:09:20Z |
| format | Journal article |
| id | oxford-uuid:8c7564de-c946-417f-922c-befc21b8577d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:09:20Z |
| publishDate | 2019 |
| publisher | EMBO Press |
| record_format | dspace |
| spelling | oxford-uuid:8c7564de-c946-417f-922c-befc21b8577d2022-03-26T22:44:49ZChlorambucil targets BRCA1/2‐deficient tumours and counteracts PARP inhibitor resistanceJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8c7564de-c946-417f-922c-befc21b8577dEnglishSymplectic Elements at OxfordEMBO Press2019Tacconi, EBadie, SDe Gregoriis, GReisländer, TLai, XPorru, MFolio, CMoore, JKopp, ABaguña Torres, JSneddon, DGreen, MDedic, SLee, JBatra, ARueda, OBruna, ALeonetti, CCaldas, CCornelissen, BBrino, LRyan, ABiroccio, ATarsounas, MDue 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. |
| spellingShingle | Tacconi, E Badie, S De Gregoriis, G Reisländer, T Lai, X Porru, M Folio, C Moore, J Kopp, A Baguña Torres, J Sneddon, D Green, M Dedic, S Lee, J Batra, A Rueda, O Bruna, A Leonetti, C Caldas, C Cornelissen, B Brino, L Ryan, A Biroccio, A Tarsounas, M Chlorambucil targets BRCA1/2‐deficient tumours and counteracts PARP inhibitor resistance |
| 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 |
| work_keys_str_mv | AT tacconie chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT badies chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT degregoriisg chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT reislandert chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT laix chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT porrum chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT folioc chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT moorej chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT koppa chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT bagunatorresj chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT sneddond chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT greenm chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT dedics chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT leej chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT batraa chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT ruedao chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT brunaa chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT leonettic chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT caldasc chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT cornelissenb chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT brinol chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT ryana chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT biroccioa chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance AT tarsounasm chlorambuciltargetsbrca12deficienttumoursandcounteractsparpinhibitorresistance |