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EMBO Mol Med. 2019 Jul;11(7):e9982. doi: 10.15252/emmm.201809982. Epub 2019 May 24.

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

Author information

1
Genome Stability and Tumorigenesis Group, Department of Oncology, The CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
2
Area of Translational Research, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
3
Lung Cancer Translational Science Research Group, Department of Oncology, The CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
4
Institut de Génétique et de Biologie Cellulaire et Moléculaire (IGBMC), Inserm U1258, CNRS (UMR 7104), Université de Strasbourg, Illkirch, France.
5
Radiopharmaceuticals and Molecular Imaging Group, Department of Oncology, The CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
6
Department of Oncology, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.

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.

KEYWORDS:

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

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