2 research outputs found
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 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.This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie SkĆodowskaâCurie grant agreement No. 722729. Research in M.T. laboratory is supported by Cancer Research UK, Medical Research Council and University of Oxford
Chlorambucil targets BRCA1/2âdeficient tumours and counteracts PARP inhibitor resistance
Abstract Due to compromised homologous recombination (HR) repair, BRCA1â and BRCA2âmutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically BRCA2âdeficient 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 BRCA1/2âdeficient cells, including olaparibâresistant and cisplatinâresistant ones, suggesting the potential clinical use of chlorambucil against disease which has become resistant to these drugs. Additionally, chlorambucil eradicates BRCA2âdeficient xenografts and inhibits growth of olaparibâresistant patientâderived tumour xenografts (PDTXs). We demonstrate that chlorambucil inflicts replicationâassociated DNA doubleâstrand 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 BRCA2âcompromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCAâdeficient tumours