Systems-Level Analysis of EGFR Inhibition-DNA Damage Combination Treatment in Breast Cancer
Annual summary rept. 1 Sep 2011-31 Aug 2012
MASSACHUSETTS INST OF TECH CAMBRIDGE
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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.
- Medicine and Medical Research