Rewiring the Networks

Sci. Signal.  15 May 2012:
Vol. 5, Issue 224, pp. ec135
DOI: 10.1126/scisignal.2003217

Because of the complexity and interconnectedness of signaling pathways, it is often difficult to predict how the therapeutic targeting of a single component will affect the overall response of the treated cell (see commentary by Erler and Linding). This is even more relevant for tumor cells, in which oncogenic factors can cause rewiring of signaling networks. Chemotherapeutic agents that induce the DNA damage response (DDR) are typically used to kill tumor cells; however, the effects of aberrant growth factor signaling, for example, can lead to resistance. Lee et al. took a systems-level approach to examine the interplay between growth factor signaling and the DDR in triple-negative breast cancer (TNBC) cells, which respond poorly to standard therapies. Multiple combinations of chemotherapeutic agents and inhibitors of signaling pathways were compared in terms of dosage and timing, and the effects of these treatments on the viability, proliferation, and apoptosis of the TNBC cells were assessed. The greatest extent of apoptosis was caused by pretreatment with inhibitors of epidermal growth factor receptor (EGFR) signaling before treatment with the DNA-damaging agent doxorubicin; simultaneous treatment with these compounds was not as potent. Prolonged (6 hours) EGFR inhibition led to changes in the expression of many genes, which suggested that the oncogenic potential of some TNBC cells is dependent on EGFR signaling. Various signaling components were assessed by protein microarrays and Western blotting analysis, enabling the authors to construct mathematical models to describe the cellular phenotypes. Some models predicted that enhanced apoptosis after EGFR inhibition was mediated by caspase 8 activation, which was suppressed by oncogenic EGFR signaling, and this prediction was experimentally verified. Finally, the staggered application of EGFR inhibitor and doxorubicin induced cell death in lung cancer cell lines in a capase 8–dependent manner. Together, these data suggest that the timed application of signaling inhibitors causes the rewiring of signaling pathways in tumor cells and makes them more susceptible to subsequent DDR-inducing therapy.

M. J. Lee, A. S. Ye, A. K. Gardino, A. M. Heijink, P. K. Sorger, G. MacBeath, M. B. Yaffe, Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell 149, 780–794 (2012). [Online Journal]

J. T. Erler, R. Linding, Network medicine strikes a blow against breast cancer. Cell 149, 731–733 (2012). [Online Journal]