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

Eliana Mc Tacconi1, Sophie Badie1, Giuliana De Gregoriis1

  • 1Genome Stability and Tumorigenesis Group, Department of Oncology, The CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.

EMBO Molecular Medicine
|July 6, 2019
PubMed

Insights

Chlorambucil specifically targets BRCA1/2-deficient tumors, including resistant types, with less toxicity than cisplatin. This alkylating agent shows promise for treating BRCA-mutated cancers, offering a better therapeutic index.

Area of Science:

  • Oncology
  • Cancer Biology
  • Genetics

Background:

  • BRCA1/2 mutations impair homologous recombination (HR) DNA repair, leading to genomic instability in tumors.
  • Targeting DNA repair deficiencies presents a therapeutic strategy for BRCA-mutated cancers.

Purpose of the Study:

  • To identify clinically approved drugs that selectively kill BRCA2-deficient cancer cells.
  • To evaluate chlorambucil as a potential therapeutic agent for BRCA-deficient and drug-resistant tumors.

Main Methods:

  • Screened a library of clinical compounds for toxicity against BRCA2-deficient cells.
  • Assessed chlorambucil's efficacy and toxicity in vitro and in vivo using cell lines and xenografts.
  • Investigated mechanisms of sensitivity and resistance involving DNA repair pathways.

Main Results:

  • Chlorambucil was identified as a potent agent against BRCA1/2-deficient cells, including those resistant to olaparib and cisplatin.
  • Chlorambucil eradicated BRCA2-deficient xenografts and inhibited resistant tumor growth.
  • Chlorambucil induces replication-associated DNA double-strand breaks and demonstrates a higher therapeutic index than cisplatin in BRCA-deficient models.

Conclusions:

  • Chlorambucil is a promising drug for treating BRCA-deficient tumors, including those resistant to PARP inhibitors and platinum-based chemotherapy.
  • Chlorambucil offers a superior therapeutic index compared to cisplatin for targeting BRCA-mutated cancers.
  • ATR, FANCD2, and SNM1A are key determinants of sensitivity to chlorambucil and cisplatin in BRCA-deficient contexts.
Keywords:
BRCA1BRCA2DNA damage responsesalkylating agentscisplatin

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