Dynamic re-wiring of apoptotic signaling networks enhances tumor cell killing by DNA damage

Understanding the architecture of oncogenic signaling pathways, and how these networks are re-wired by ligands or drugs, could provide opportunities for the specific targeting of oncogene-driven tumors. Here we use a systems biology-based approach to explore synergistic therapeutic strategies to optimize the killing of triple negative breast cancer cells, an incompletely understood tumor type with a poor treatment outcome. Using targeted inhibition of oncogenic signaling pathways combined with DNA damaging chemotherapy, we report the surprising finding that time-staggered EGFR inhibition, but not simultaneous co-administration, can dramatically sensitize the apoptotic response of a subset of triple-negative cells to conventional DNA damaging agents. A systematic analysis of the order and timing of inhibitor/genotoxin presentation—using a combination of high-density time-dependent activity measurements of signaling networks, gene expression profiles, cell phenotypic responses, and mathematical modeling—revealed an approach for altering the intrinsic oncogenic state of the cell through dynamic re-wiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death, through re-activation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state.