Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks.

TitleSequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks.
Publication TypeJournal Article
Year of Publication2012
AuthorsLee, MJ, Ye, AS, Gardino, AK, Heijink, AMargriet, Sorger, PK, MacBeath, G, Yaffe, MB
JournalCell
Volume149
Issue4
Pagination780-94
Date Published2012 May 11
ISSN1097-4172
KeywordsAntineoplastic Agents, Apoptosis, Breast Neoplasms, Caspase 8, Cell Line, Tumor, DNA Damage, Drug Therapy, Combination, Female, Humans, Metabolic Networks and Pathways, Models, Biological, Receptor, Epidermal Growth Factor, Signal Transduction
Abstract

Crosstalk and complexity within signaling pathways and their perturbation by oncogenes limit component-by-component approaches to understanding human disease. Network analysis of how normal and oncogenic signaling can be rewired by drugs may provide opportunities to target tumors with high specificity and efficacy. Using targeted inhibition of oncogenic signaling pathways, combined with DNA-damaging chemotherapy, we report that time-staggered EGFR inhibition, but not simultaneous coadministration, dramatically sensitizes a subset of triple-negative breast cancer cells to genotoxic drugs. Systems-level analysis-using high-density time-dependent measurements of signaling networks, gene expression profiles, and cell phenotypic responses in combination with mathematical modeling-revealed an approach for altering the intrinsic state of the cell through dynamic rewiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death by reactivation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state.

DOI10.1016/j.cell.2012.03.031
Alternate JournalCell
PubMed ID22579283
PubMed Central IDPMC3501264
Grant ListCA112967 / CA / NCI NIH HHS / United States
ES015339 / ES / NIEHS NIH HHS / United States
GM68762 / GM / NIGMS NIH HHS / United States
P50 GM068762 / GM / NIGMS NIH HHS / United States
R01 ES015339 / ES / NIEHS NIH HHS / United States
U54 CA112967 / CA / NCI NIH HHS / United States