Limited inhibition of multiple nodes in a driver network blocks metastasis
Metastasis suppression by high-dose, multi-drug targeting is unsuccessful due to network heterogeneity and compensatory network activation. Here, we show that targeting driver network signaling capacity by limited inhibition of core pathways is a more effective anti-metastatic strategy. This princip...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-05-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/59696 |
| _version_ | 1811180407661527040 |
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| author | Ali Ekrem Yesilkanal Dongbo Yang Andrea Valdespino Payal Tiwari Alan U Sabino Long Chi Nguyen Jiyoung Lee Xiao-He Xie Siqi Sun Christopher Dann Lydia Robinson-Mailman Ethan Steinberg Timothy Stuhlmiller Casey Frankenberger Elizabeth Goldsmith Gary L Johnson Alexandre F Ramos Marsha R Rosner |
| author_facet | Ali Ekrem Yesilkanal Dongbo Yang Andrea Valdespino Payal Tiwari Alan U Sabino Long Chi Nguyen Jiyoung Lee Xiao-He Xie Siqi Sun Christopher Dann Lydia Robinson-Mailman Ethan Steinberg Timothy Stuhlmiller Casey Frankenberger Elizabeth Goldsmith Gary L Johnson Alexandre F Ramos Marsha R Rosner |
| author_sort | Ali Ekrem Yesilkanal |
| collection | DOAJ |
| description | Metastasis suppression by high-dose, multi-drug targeting is unsuccessful due to network heterogeneity and compensatory network activation. Here, we show that targeting driver network signaling capacity by limited inhibition of core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein (RKIP), that moderately decreases stress-regulated MAP kinase network activity, reducing output to transcription factors such as pro-metastastic BACH1 and motility-related target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells. Restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically relevant strategy for anti-metastatic treatment. |
| first_indexed | 2024-04-11T09:01:38Z |
| format | Article |
| id | doaj.art-4ff20943f44747458fc45b3108f69f89 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:01:38Z |
| publishDate | 2021-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4ff20943f44747458fc45b3108f69f892022-12-22T04:32:45ZengeLife Sciences Publications LtdeLife2050-084X2021-05-011010.7554/eLife.59696Limited inhibition of multiple nodes in a driver network blocks metastasisAli Ekrem Yesilkanal0https://orcid.org/0000-0003-4988-1294Dongbo Yang1Andrea Valdespino2Payal Tiwari3Alan U Sabino4https://orcid.org/0000-0003-1094-5078Long Chi Nguyen5Jiyoung Lee6https://orcid.org/0000-0001-8503-4805Xiao-He Xie7Siqi Sun8Christopher Dann9Lydia Robinson-Mailman10Ethan Steinberg11Timothy Stuhlmiller12Casey Frankenberger13Elizabeth Goldsmith14Gary L Johnson15https://orcid.org/0000-0003-2867-0551Alexandre F Ramos16Marsha R Rosner17https://orcid.org/0000-0001-6586-8335Ben May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesInstituto do Câncer do Estado de São Paulo, Faculdade de Medicina and Escola de Artes, Ciências e Humanidades; University of São Paulo, São Paulo, BrazilBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesUT Southwestern, Dallas, United StatesDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United StatesInstituto do Câncer do Estado de São Paulo, Faculdade de Medicina and Escola de Artes, Ciências e Humanidades; University of São Paulo, São Paulo, BrazilBen May Department for Cancer Research, University of Chicago, Chicago, United StatesMetastasis suppression by high-dose, multi-drug targeting is unsuccessful due to network heterogeneity and compensatory network activation. Here, we show that targeting driver network signaling capacity by limited inhibition of core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein (RKIP), that moderately decreases stress-regulated MAP kinase network activity, reducing output to transcription factors such as pro-metastastic BACH1 and motility-related target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells. Restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically relevant strategy for anti-metastatic treatment.https://elifesciences.org/articles/59696metastasisMAPKraf kinase inhibitory proteinBACH1drug combinationsmathematical modeling |
| spellingShingle | Ali Ekrem Yesilkanal Dongbo Yang Andrea Valdespino Payal Tiwari Alan U Sabino Long Chi Nguyen Jiyoung Lee Xiao-He Xie Siqi Sun Christopher Dann Lydia Robinson-Mailman Ethan Steinberg Timothy Stuhlmiller Casey Frankenberger Elizabeth Goldsmith Gary L Johnson Alexandre F Ramos Marsha R Rosner Limited inhibition of multiple nodes in a driver network blocks metastasis eLife metastasis MAPK raf kinase inhibitory protein BACH1 drug combinations mathematical modeling |
| title | Limited inhibition of multiple nodes in a driver network blocks metastasis |
| title_full | Limited inhibition of multiple nodes in a driver network blocks metastasis |
| title_fullStr | Limited inhibition of multiple nodes in a driver network blocks metastasis |
| title_full_unstemmed | Limited inhibition of multiple nodes in a driver network blocks metastasis |
| title_short | Limited inhibition of multiple nodes in a driver network blocks metastasis |
| title_sort | limited inhibition of multiple nodes in a driver network blocks metastasis |
| topic | metastasis MAPK raf kinase inhibitory protein BACH1 drug combinations mathematical modeling |
| url | https://elifesciences.org/articles/59696 |
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