Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks

• Published in: Cell 2012-05, Vol.149 (4), p.780-794
• Main Authors: Lee, Michael J., Ye, Albert S., Gardino, Alexandra K., Heijink, Anne Margriet, Sorger, Peter K., MacBeath, Gavin, Yaffe, Michael B.
• Format: Article
• Language: English
• Subjects: antineoplastic agents; Antineoplastic Agents - administration & dosage; Apoptosis; breast neoplasms; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Caspase 8; Cell Line, Tumor; cells; DNA; DNA Damage; drug therapy; Drug Therapy, Combination - methods; Female; gene expression; genotoxicity; human diseases; Humans; inhibition; Metabolic Networks and Pathways; Models, Biological; neoplasm cells; oncogenes; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.03.031

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. [Display omitted] ► The efficacy of combination treatments for cancer depends on drug order and timing ► Dynamic rewiring of signaling networks by drugs can provide therapeutic benefit ► Sustained EGFR inhibition sensitizes triple-negative breast cancer cells to DNA damage ► EGFR activity, but not EGFR expression, is a biomarker of response to this treatment The effectiveness of combination therapy for triple-negative breast cancer may be increased by delivering the drugs sequentially. Inhibiting EGFR dynamically rewires tumor cell signaling networks to enhance subsequent susceptibility to DNA-damaging agents, an effect not seen when the drugs are applied simultaneously.