Therapeutic targeting and patient selection for cancers with homologous recombination defects
| Autor: | Mathilde Jalving, Marcel A. T. M. van Vugt, Francien Talens, Jourik A. Gietema |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genome instability homologous recombination Synthetic lethality DOUBLE-STRAND BREAKS chemistry.chemical_compound 0302 clinical medicine BRCA2 MUTATION CARRIERS Drug Discovery DNA Breaks Double-Stranded Molecular Targeted Therapy DNA END RESECTION Ovarian Neoplasms BRCA1 Protein personalized medicine 3. Good health 030220 oncology & carcinogenesis SENSITIVE OVARIAN-CANCER PARP inhibitor Lynparza Female Context (language use) Breast Neoplasms EMBRYONIC CELLULAR PROLIFERATION Biology Poly(ADP-ribose) Polymerase Inhibitors olaparib Olaparib 03 medical and health sciences medicine Animals Humans Genetic Predisposition to Disease EX-VIVO ASSAY BRCA2 Protein FANCONI-ANEMIA PATHWAY Patient Selection Cancer Recombinational DNA Repair RANDOMIZED PHASE-2 TRIAL BRCA1 medicine.disease BRCA2 genome instability synthetic lethality NEGATIVE BREAST-CANCER 030104 developmental biology chemistry OLAPARIB MAINTENANCE THERAPY Drug Design Mutation Cancer research Ovarian cancer Homologous recombination |
| Zdroj: | Expert Opinion on Drug Discovery |
| ISSN: | 1746-0441 |
| DOI: | 10.1080/17460441.2017.1322061 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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