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


Type
Article
Change log
Authors
Tacconi, Eliana Mc 
Badie, Sophie 
De Gregoriis, Giuliana 
Lai, Xianning 
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.

Description
Keywords
BRCA1, BRCA2, DNA damage responses, alkylating agents, cisplatin, Animals, BRCA1 Protein, BRCA2 Protein, Cell Line, Tumor, Chlorambucil, Cricetinae, Drug Delivery Systems, Drug Resistance, Neoplasm, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Mice, Mice, SCID, Peroxisome Proliferator-Activated Receptors, Phthalazines, Piperazines, Xenograft Model Antitumor Assays
Journal Title
EMBO Mol Med
Conference Name
Journal ISSN
1757-4676
1757-4684
Volume Title
11
Publisher
Wiley
Sponsorship
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (60098573)
Cancer Research UK (unknown)
Cancer Research UK (CB4140)
This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No. 722729. Research in M.T. laboratory is supported by Cancer Research UK, Medical Research Council and University of Oxford.