PloS one, 2012-10, Vol.7 (10), p.e46614
2012
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- Autor(en) / Beteiligte
- Titel
- Synthetic lethal interactions between EGFR and PARP inhibition in human triple negative breast cancer cells
- Ist Teil von
- PloS one, 2012-10, Vol.7 (10), p.e46614
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Few therapeutic options exist for the highly aggressive triple negative breast cancers (TNBCs). In this study, we report that a contextual synthetic lethality can be achieved both in vitro and in vivo with combined EGFR and PARP inhibition with lapatinib and ABT-888, respectively. The mechanism involves a transient DNA double strand break repair deficit induced by lapatinib and subsequent activation of the intrinsic pathway of apoptosis. Further dissection of the mechanism reveals that EGFR and BRCA1 can be found in the same protein complex, which is reduced by lapatinib. Interestingly, lapatinib also increases cytosolic BRCA1 and EGFR, away from their nuclear DNA repair substrates. Taken together, these results reveal a novel regulation of homologous recombination repair involving EGFR and BRCA1 interaction and alteration of subcellular localization. Additionally, a contextual synthetic lethality may exist between combined EGFR and PARP inhibitors.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0046614Titel-ID: cdi_plos_journals_1326551409
- Format
- –
- Schlagworte
- Angiogenesis, Animals, Antineoplastic Agents - pharmacology, Antineoplastic Combined Chemotherapy Protocols - pharmacology, Antineoplastic Combined Chemotherapy Protocols - therapeutic use, Apoptosis, Apoptosis - drug effects, Benzimidazoles - administration & dosage, Biology, Biotechnology, BRCA1 protein, BRCA1 Protein - metabolism, Breast cancer, Breast Neoplasms - drug therapy, Breast Neoplasms - metabolism, Breast Neoplasms - pathology, Cancer cells, Cancer therapies, Cell cycle, Cell Line, Tumor - drug effects, Cell Nucleus - drug effects, Cell Nucleus - metabolism, Cell Survival - drug effects, Chemotherapy, Clinical trials, Cytotoxicity, Deoxyribonucleic acid, Dissection, DNA, DNA Breaks, Double-Stranded, DNA damage, DNA repair, Drug Synergism, Epidermal growth factor, Epidermal growth factor receptors, ErbB Receptors - antagonists & inhibitors, ErbB Receptors - metabolism, Experiments, Female, Homologous recombination, Homologous recombination repair, Homology, Humans, Inhibition, Kinases, Lapatinib, Lethality, Localization, Medical prognosis, Medicine, Mice, Mutation, Oncology, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) polymerase, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases - metabolism, Protein Binding, Protein Transport - drug effects, Quinazolines - administration & dosage, Receptor, ErbB-2 - metabolism, Receptors, Estrogen - metabolism, Receptors, Progesterone - metabolism, Recombinational DNA Repair - drug effects, Repair, Rodents, Substrates, Tumor Burden - drug effects, Tumors, Xenograft Model Antitumor Assays