Therapeutic targeting and patient selection for cancers with homologous recombination defects

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Abstract

Introduction: DNA double-strand breaks (DSBs) are toxic DNA lesions that can be repaired by non-homologous end-joining (NHEJ) or homologous recombination (HR). Mutations in HR genes elicit a predisposition to cancer; yet, they also result in increased sensitivity to certain DNA damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors. To optimally implement PARP inhibitor treatment, it is important that patients with HR-deficient tumors are adequately selected.

Areas covered: Herein, the authors describe the HR pathway mechanistically and review the treatment of HR-deficient cancers, with a specific focus on PARP inhibition for BRCA1/2-mutated breast and ovarian cancer. In addition, mechanisms of acquired PARP inhibitor resistance are discussed. Furthermore, combination therapies with PARP inhibitors are reviewed, in the context of both HR-deficient and HR-proficient tumors and methods for proper patient selection are also discussed.

Expert opinion: Currently, only patients with germline or somatic BRCA1/2 mutations are eligible for PARP inhibitor treatment and only a proportion of patients respond. Patients with HR-deficient tumors caused by other (epi)genetic events may also benefit from PARP inhibitor treatment. Ideally, selection of eligible patients for PARP inhibitor treatment include a functional HR read-out, in which cancer cells are interrogated for their ability to perform HR repair and maintain replication fork stability.

Original languageEnglish
Pages (from-to)565-581
Number of pages17
JournalExpert Opinion on Drug Discovery
Volume12
Issue number6
DOIs
Publication statusPublished - Jun-2017

Keywords

  • BRCA1
  • BRCA2
  • genome instability
  • homologous recombination
  • Lynparza
  • olaparib
  • PARP inhibitor
  • personalized medicine
  • synthetic lethality
  • NEGATIVE BREAST-CANCER
  • DNA END RESECTION
  • DOUBLE-STRAND BREAKS
  • EMBRYONIC CELLULAR PROLIFERATION
  • OLAPARIB MAINTENANCE THERAPY
  • RANDOMIZED PHASE-2 TRIAL
  • SENSITIVE OVARIAN-CANCER
  • BRCA2 MUTATION CARRIERS
  • FANCONI-ANEMIA PATHWAY
  • EX-VIVO ASSAY

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