Synthetic Lethal Interactions Between EGFR and PARP Inhibition in Human Triple Negative Breast Cancer Cells

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Oct 17

PMID 23071597

Citations 61

Authors

Somaira Nowsheen

Tiffiny Cooper

Jennifer A Stanley

Eddy S Yang

Affiliations

Soon will be listed here.

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.

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