Journal
PLOS ONE
Volume 7, Issue 10, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0046614
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Funding
- UAB Specialized Programs of Research Excellence (SPORE) in breast cancer [5P50CA089019-10]
- Translational Scholar Award from Sidney Kimmel Foundation
- Breast Cancer Research Foundation of Alabama
- State of Alabama Investment Pool for Action (IMPACT) Award from the University of Alabama at Birmingham School of Medicine
- Comprehensive Cancer Center and Department of Radiation Oncology at the University of Alabama at Birmingham School of Medicine
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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.
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