Cell 149, 780–794 (2012)

New strategies to treat triple-negative breast cancers (TNBCs), which lack estrogen receptor or progesterone receptor expression and amplification of HER2, are needed. To determine whether manipulation of growth factor signaling can influence the sensitivity of TNBCs to DNA-damaging agents, Lee et al. combined genotoxic drugs with small molecules that target oncogenic pathways and compared outcomes in TNBC cells to those in other breast cancer cell lines. Combinations in which the EGFR inhibitor erlotinib was added to cells for several hours before addition of the genotoxic agent enhanced apoptosis. The authors validated that the increase in apoptosis resulted from the on-target activity of erlotinib by using other EGFR inhibitors and short interfering RNA (siRNA) knockdown of EGFR. After ruling out changes in cell cycle progression, drug influx or efflux and changes in DNA damage, they showed that prolonged EGFR inhibition suppressed a Ras oncogene expression signature to enhance DNA damage-induced cell death. The authors used a multiplex systems biology approach to quantify 35 signaling proteins at various time points after treatment with erlotinib, genotoxic agent or both; an iterative mathematical modeling analysis of these data revealed that caspase-8 was the most important mediator of apoptosis. siRNA knockdown confirmed that caspase-8 was critical for the apoptotic response. These data indicate that pretreatment but not co-treatment of some TNBCs with EGFR inhibitors can rewire signaling networks and unmask proapoptotic pathways, thereby synergizing with genotoxic agents to induce apoptosis.