Chlorambucil targets BRCA1/2-deficient tumours and counteracts PARP inhibitor resistance.
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Date
2019-07-01ICR Author
Author
Tacconi, EM
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, JW
Batra, AS
Rueda, OM
Bruna, A
Leonetti, C
Caldas, C
Cornelissen, B
Brino, L
Ryan, A
Biroccio, A
Tarsounas, M
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Animals
Humans
Mice
Mice, SCID
Chlorambucil
Piperazines
Phthalazines
BRCA1 Protein
BRCA2 Protein
Peroxisome Proliferator-Activated Receptors
Drug Delivery Systems
Xenograft Model Antitumor Assays
Drug Resistance, Neoplasm
Cricetinae
Male
Leukemia, Lymphocytic, Chronic, B-Cell
Research team
Preclinical Modelling of Paediatric Cancer Evolution
Language
eng
Date accepted
2019-05-03
License start date
2019-07
Citation
EMBO molecular medicine, 2019, 11 (7), pp. e9982 - ?
Publisher
WILEY