Pretreatment with EGFR inhibitors sensitizes triple-negative breast cancers to cytotoxic agents.
Major finding: Pretreatment with EGFR inhibitors sensitizes triple-negative breast cancers to cytotoxic agents.
Concept: EGFR inhibitors rewire an EGFR-driven signaling network to derepress apoptotic pathways.
Impact: Time-staggered treatment protocols may be generalizable to other oncogene-addicted cancers.
Unlike other breast cancer subtypes overexpressing the estrogen or progesterone receptors or harboring a HER2 amplification, triple-negative breast cancers (TNBC) do not respond to conventional hormonal or targeted treatment regimens and consequently have a worse overall prognosis. Lee and colleagues reasoned that new treatment strategies might be identified by systematic analysis of the effects of various doses and schedules of cytotoxic and targeted therapy combinations on the viability and proliferation of TNBC cells. Surprisingly, administration of the epidermal growth factor receptor (EGFR) inhibitor erlotinib several hours prior to the cytotoxic agent doxorubicin enhanced the doxorubicin sensitivity of 9 out of 10 TNBC cell lines and reduced the size of TNBC xenograft tumors. This effect was not observed when doxorubicin was added before or at the same time as erlotinib or in other breast cancer subtypes. In TNBC cells, continuous erlotinib treatment led to progressive, widespread changes in gene expression and signaling proteins, with mathematical models indicating that EGFR inhibition leads to rewiring of an EGFR-mediated network that culminates in activation of apoptotic responses. Importantly, this time-dependent response was also observed in TNBC cells with combinations of other EGFR inhibitors and cytotoxic drugs as well as in other cancer cell types with high levels of EGFR activity. Furthermore, the doxorubicin sensitivity of breast cancer cells known to be addicted to HER2 could also be enhanced by pretreatment with the dual HER2–EGFR inhibitor lapatinib. Collectively, these results identify a potential treatment regimen for TNBC and raise the exciting possibility that the time-staggered use of targeted therapies to sensitize cancers to subsequent chemotherapy may be a generalizable therapeutic strategy that will improve clinical outcome.
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