Systems-Level Analysis of EGFR Inhibition-DNA Damage Combination Treatment in Breast Cancer.

摘要

Triple-negative breast cancer (TNBC) is a heterogeneous mix of cancers defined only by the absence of the three best-characterized prognostic markers: estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). This lack of understanding underlies our inability to identify effective therapeutic options for these patients. During the previous research period for this award (year 1), we identified that a subset of TNBCs have high baseline levels of activated EGFR, and were sensitive to certain temporal combinations of EGFR inhibition and DNA damaging chemotherapy. The focus of this research period (year 2) was to determine the mechanism of this enhanced sensitivity to chemotherapy. Using an integrative analysis of multiple signaling networks, we identified that chronic exposure to EGFR inhibition in a subset of TNBCs resulted in a profound genetic rewiring, resulting in more than 2000 differentially expressed genes (DEGs). Further analyses revealed that caspase-8 played a crucial role in the combination therapy we identified, a surprising and unexpected finding, since this protein was not previously thought to contribute to DNA damage-induced cell death. Collectively, these findings identify a novel method for enhancing chemotherapeutic efficacy, through rewiring apoptotic signaling networks.