Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks
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 specifici...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
| Published: |
Elsevier
2014
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| Online Access: | http://hdl.handle.net/1721.1/91688 https://orcid.org/0000-0002-9547-3251 |
| _version_ | 1811069127695007744 |
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| author | Lee, Michael J. Ye, Albert S. Gardino, Alexandra Kate Heijink, Anne Margriet Sorger, Peter K. MacBeath, Gavin Yaffe, Michael B. Sorger, Peter K. Yaffe, Michael B. |
| author2 | Massachusetts Institute of Technology. Cell Decision Process Center |
| author_facet | Massachusetts Institute of Technology. Cell Decision Process Center Lee, Michael J. Ye, Albert S. Gardino, Alexandra Kate Heijink, Anne Margriet Sorger, Peter K. MacBeath, Gavin Yaffe, Michael B. Sorger, Peter K. Yaffe, Michael B. |
| author_sort | Lee, Michael J. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T08:06:08Z |
| format | Article |
| id | mit-1721.1/91688 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:06:08Z |
| publishDate | 2014 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/916882022-09-30T07:31:05Z Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks Lee, Michael J. Ye, Albert S. Gardino, Alexandra Kate Heijink, Anne Margriet Sorger, Peter K. MacBeath, Gavin Yaffe, Michael B. Sorger, Peter K. Yaffe, Michael B. Massachusetts Institute of Technology. Cell Decision Process Center Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Lee, Michael J. Ye, Albert S. Gardino, Alexandra Kate Heijink, Anne Margriet Sorger, Peter K. MacBeath, Gavin Yaffe, Michael B. 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. National Institutes of Health (U.S.) (Grant CA112967) National Institutes of Health (U.S.) (Grant GM68762) National Institutes of Health (U.S.) (Grant ES015339) United States. Dept. of Defense (Fellowship BC097884) 2014-11-24T14:45:59Z 2014-11-24T14:45:59Z 2012-05 2011-12 Article http://purl.org/eprint/type/JournalArticle 00928674 1097-4172 http://hdl.handle.net/1721.1/91688 Lee, Michael J., Albert S. Ye, Alexandra K. Gardino, Anne Margriet Heijink, Peter K. Sorger, Gavin MacBeath, and Michael B. Yaffe. “Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks.” Cell 149, no. 4 (May 2012): 780–794. © 2012 Elsevier Inc. https://orcid.org/0000-0002-9547-3251 en_US http://dx.doi.org/10.1016/j.cell.2012.03.031 Cell Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier |
| spellingShingle | Lee, Michael J. Ye, Albert S. Gardino, Alexandra Kate Heijink, Anne Margriet Sorger, Peter K. MacBeath, Gavin Yaffe, Michael B. Sorger, Peter K. Yaffe, Michael B. Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks |
| title | Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks |
| title_full | Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks |
| title_fullStr | Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks |
| title_full_unstemmed | Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks |
| title_short | Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks |
| title_sort | sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks |
| url | http://hdl.handle.net/1721.1/91688 https://orcid.org/0000-0002-9547-3251 |
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