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

Abstract

Due to compromised homologous recombination ( HR ) repair, BRCA 1‐ and BRCA 2‐ mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically BRCA 2‐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 BRCA 1/2‐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 BRCA 2‐deficient xenografts and inhibits growth of olaparib‐resistant patient‐derived tumour xenografts ( PDTX s). We demonstrate that chlorambucil inflicts replication‐associated DNA double‐strand breaks ( DSB s), similarly to cisplatin, and we identify ATR , FANCD 2 and the SNM 1A 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 BRCA 2‐compromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCA ‐deficient tumours.

Brca2 deficiency drives gastrointestinal tumor formation and is selectively inhibited by mitomycin C

“…S2b-S2e). Consistent with previous reports 46 , 1 µM olaparib treatment for 5 days significantly decreased about 50% of the viability of HGC-27 cells ( Fig. S2f).…”

Effect of sodium butyrate on ABC transporters in lung cancer A549 and colorectal cancer HCT116 cells

“…The combination of NaB with DNA alkylating agents and/or other MRP1-3 substrates may lead to synergistic and more efficacious treatments. For instance, chlorambucil exerts its antitumor activity in variety of cancer cells, including lymphocytic leukemia, ovarian cancer, colorectal cancer and lung cancer (35,36). In the current study, the combination of NaB and chlorambucil exerted a synergistic effect in colorectal cancer and lung cancer.…”

Aromatic Linkers Unleash the Antiproliferative Potential of 3‐Chloropiperidines Against Pancreatic Cancer Cells

“…Nevertheless, studies are ongoing to reveal which distinctive mechanisms prior or following DNA damage are responsible for the unexpected activity of aromatic B−CePs against BxPC‐3 pancreatic cancer cells. Preferential targeting by nitrogen mustards has recently been reported for chlorambucil against BRCA 1/2‐deficient tumors, thus demonstrating that even agents commonly known as aspecific could exhibit cancer type tropisms [17] . In this sense, we plan to employ an omic approach to elucidate the molecular determinants of sensitivity for aromatic 3‐chloropiperidines against BxPC‐3 cells.…”