Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibition provides a promising therapeutic modality for targeting homologous recombination (HR) deficient tumors such as BRCA1 and BRCA2-mutated triple negative breast cancers (TNBCs). Although PARP inhibitors have shown activity in the BRCA-associated TNBCs, several of these tumors develop de novo as well as acquired PARP inhibitor (PARPi) resistance. Besides attenuation in intracellular uptake of drugs, the only known mechanism that drives chemotherapy resistance of BRCA1/2-deficient cancers is through the restoration of HR. Recent studies from our laboratories (Nussenzweig and DAndrea) indicate that deregulation of pathways that promote extensive degradation of nascent DNA strands and alternative end-joining (Alt-EJ) can render BRCA1/2-deficient cells resistant to PARPi in a HR-independent manner. The objective of our project is to collaboratively test the hypothesis that complex processes involving Alt-EJ or replication fork stability promote survival and drives resistance to chemotherapy.

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Document Details

Document Type
Technical Report
Publication Date
Oct 01, 2019
Accession Number
AD1095203

Entities

People

  • Andre Nussenzweig

Organizations

  • Geneva Foundation

Tags

DTIC Thesaurus Topics

  • Biology
  • Biomedical Research
  • Breast Cancer
  • Chemotherapy
  • Department Of Defense
  • Drug Resistance
  • Genes
  • Genetic Phenomena
  • Genetic Structures
  • Genetics
  • Genome
  • Inhibition
  • Lethality
  • Mutations
  • Neoplasms
  • Standards
  • Therapy

Fields of Study

  • Biology
  • Medicine

Readers

  • Molecular Biology and Genetics
  • Oncology (Cancer Research).