Chlorambucil targets BRCA1/2-deficient tumours and counteracts PARP inhibitor resistance

Eliana M.C. 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 CornelissenLaurent Brino, Anderson Ryan, Annamaria Biroccio, Madalena Tarsounas

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)e9982
JournalEMBO Molecular Medicine
Volume11
Issue number7
DOIs
Publication statusPublished - Jul 2019

Keywords

  • alkylating agents
  • BRCA1
  • BRCA2
  • cisplatin
  • DNA damage responses

ASJC Scopus subject areas

  • Molecular Medicine

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  • Cite this

    Tacconi, E. M. C., 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. W., Batra, A. S., Rueda, O. M., Bruna, A., Leonetti, C., Caldas, C., ... Tarsounas, M. (2019). Chlorambucil targets BRCA1/2-deficient tumours and counteracts PARP inhibitor resistance. EMBO Molecular Medicine, 11(7), e9982. https://doi.org/10.15252/emmm.201809982