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

UMMS Affiliation

Program in Systems Biology

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Antineoplastic 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


Biochemistry | Cell Biology | Computational Biology | Molecular Biology | Systems Biology


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.

DOI of Published Version



Lee MJ, Ye AS, Gardino AK, Heijink AM, Sorger PK, MacBeath G, Yaffe MB. Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell. 2012 May 11;149(4):780-94. doi: 10.1016/j.cell.2012.03.031. Link to article on publisher's site

Journal/Book/Conference Title



At the time of publication, Michael J. Lee was not yet affiliated with the University of Massachusetts Medical School.

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