Chlorambucil targets BRCA 1/2‐deficient tumours and counteracts PARP inhibitor resistance

• DOI: 10.15252/emmm.201809982
• Publication Date: 2019-05-24T13:55:12Z
• Authors: Eliana MC Tacconi; Sophie Badie; Giuliana De Grego...; 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 Cornelissen; Laurent Brino; Anderson Ryan; Annamaria Biroccio; Madalena Tarsounas
• Keywords: Male; 0301 basic medicine; Medicine (General); Peroxisome Proliferator-Activated Receptors; Drug Resistance; cisplatin; Mice, SCID; QH426-470; SCID; Piperazines; Cell Line; Mice; 03 medical and health sciences; R5-920; Drug Delivery Systems; Cell Line, Tumor; Cricetinae; 616; alkylating agents; [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology; Genetics; Animals; Humans; Chronic; BRCA2 Protein; Tumor; Leukemia; BRCA1 Protein; B-Cell; Articles; BRCA1; BRCA2; Leukemia, Lymphocytic, Chronic, B-Cell; Xenograft Model Antitumor Assays; Lymphocytic; 3. Good health; Drug Resistance, Neoplasm; Neoplasm; Phthalazines; Chlorambucil; DNA damage responses

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.