1. Synthetic Lethal Interactions between EGFR and PARP Inhibition in Human Triple Negative Breast Cancer Cells
- Author
-
Jennifer A. Stanley, Eddy S. Yang, Somaira Nowsheen, and Tiffiny Cooper
- Subjects
Anatomy and Physiology ,Receptor, ErbB-2 ,Cancer Treatment ,Poly (ADP-Ribose) Polymerase-1 ,lcsh:Medicine ,Gene Expression ,Apoptosis ,Synthetic lethality ,Poly (ADP-Ribose) Polymerase Inhibitor ,Mice ,0302 clinical medicine ,Endocrinology ,Breast Tumors ,Basic Cancer Research ,Antineoplastic Combined Chemotherapy Protocols ,DNA Breaks, Double-Stranded ,lcsh:Science ,skin and connective tissue diseases ,Triple-negative breast cancer ,0303 health sciences ,Multidisciplinary ,BRCA1 Protein ,Obstetrics and Gynecology ,Drug Synergism ,3. Good health ,Tumor Burden ,ErbB Receptors ,Protein Transport ,Oncology ,Receptors, Estrogen ,030220 oncology & carcinogenesis ,Medicine ,Oncology Agents ,Female ,Poly(ADP-ribose) Polymerases ,Receptors, Progesterone ,medicine.drug ,Research Article ,Protein Binding ,DNA repair ,DNA damage ,Cell Survival ,Poly ADP ribose polymerase ,Endocrine System ,Antineoplastic Agents ,Breast Neoplasms ,Biology ,Poly(ADP-ribose) Polymerase Inhibitors ,Lapatinib ,03 medical and health sciences ,Cell Line, Tumor ,Breast Cancer ,medicine ,Genetics ,Animals ,Humans ,030304 developmental biology ,Cell Nucleus ,Endocrine Physiology ,Epidermal Growth Factor ,lcsh:R ,Cancers and Neoplasms ,Recombinational DNA Repair ,Molecular biology ,Xenograft Model Antitumor Assays ,Cancer research ,Quinazolines ,lcsh:Q ,Benzimidazoles ,Gene Function ,Homologous recombination - Abstract
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.
- Published
- 2012