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Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer
Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617294/ https://www.ncbi.nlm.nih.gov/pubmed/34824367 http://dx.doi.org/10.1038/s42003-021-02842-3 |
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author | Joshi, Suhasini Gomes, Erica DaGama Wang, Tai Corben, Adriana Taldone, Tony Gandu, Srinivasa Xu, Chao Sharma, Sahil Buddaseth, Salma Yan, Pengrong Chan, Lon Yin L. Gokce, Askan Rajasekhar, Vinagolu K. Shrestha, Lisa Panchal, Palak Almodovar, Justina Digwal, Chander S. Rodina, Anna Merugu, Swathi Pillarsetty, NagaVaraKishore Miclea, Vlad Peter, Radu I. Wang, Wanyan Ginsberg, Stephen D. Tang, Laura Mattar, Marissa de Stanchina, Elisa Yu, Kenneth H. Lowery, Maeve Grbovic-Huezo, Olivera O’Reilly, Eileen M. Janjigian, Yelena Healey, John H. Jarnagin, William R. Allen, Peter J. Sander, Chris Erdjument-Bromage, Hediye Neubert, Thomas A. Leach, Steven D. Chiosis, Gabriela |
author_facet | Joshi, Suhasini Gomes, Erica DaGama Wang, Tai Corben, Adriana Taldone, Tony Gandu, Srinivasa Xu, Chao Sharma, Sahil Buddaseth, Salma Yan, Pengrong Chan, Lon Yin L. Gokce, Askan Rajasekhar, Vinagolu K. Shrestha, Lisa Panchal, Palak Almodovar, Justina Digwal, Chander S. Rodina, Anna Merugu, Swathi Pillarsetty, NagaVaraKishore Miclea, Vlad Peter, Radu I. Wang, Wanyan Ginsberg, Stephen D. Tang, Laura Mattar, Marissa de Stanchina, Elisa Yu, Kenneth H. Lowery, Maeve Grbovic-Huezo, Olivera O’Reilly, Eileen M. Janjigian, Yelena Healey, John H. Jarnagin, William R. Allen, Peter J. Sander, Chris Erdjument-Bromage, Hediye Neubert, Thomas A. Leach, Steven D. Chiosis, Gabriela |
author_sort | Joshi, Suhasini |
collection | PubMed |
description | Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks. |
format | Online Article Text |
id | pubmed-8617294 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86172942021-12-10 Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer Joshi, Suhasini Gomes, Erica DaGama Wang, Tai Corben, Adriana Taldone, Tony Gandu, Srinivasa Xu, Chao Sharma, Sahil Buddaseth, Salma Yan, Pengrong Chan, Lon Yin L. Gokce, Askan Rajasekhar, Vinagolu K. Shrestha, Lisa Panchal, Palak Almodovar, Justina Digwal, Chander S. Rodina, Anna Merugu, Swathi Pillarsetty, NagaVaraKishore Miclea, Vlad Peter, Radu I. Wang, Wanyan Ginsberg, Stephen D. Tang, Laura Mattar, Marissa de Stanchina, Elisa Yu, Kenneth H. Lowery, Maeve Grbovic-Huezo, Olivera O’Reilly, Eileen M. Janjigian, Yelena Healey, John H. Jarnagin, William R. Allen, Peter J. Sander, Chris Erdjument-Bromage, Hediye Neubert, Thomas A. Leach, Steven D. Chiosis, Gabriela Commun Biol Article Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks. Nature Publishing Group UK 2021-11-25 /pmc/articles/PMC8617294/ /pubmed/34824367 http://dx.doi.org/10.1038/s42003-021-02842-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Joshi, Suhasini Gomes, Erica DaGama Wang, Tai Corben, Adriana Taldone, Tony Gandu, Srinivasa Xu, Chao Sharma, Sahil Buddaseth, Salma Yan, Pengrong Chan, Lon Yin L. Gokce, Askan Rajasekhar, Vinagolu K. Shrestha, Lisa Panchal, Palak Almodovar, Justina Digwal, Chander S. Rodina, Anna Merugu, Swathi Pillarsetty, NagaVaraKishore Miclea, Vlad Peter, Radu I. Wang, Wanyan Ginsberg, Stephen D. Tang, Laura Mattar, Marissa de Stanchina, Elisa Yu, Kenneth H. Lowery, Maeve Grbovic-Huezo, Olivera O’Reilly, Eileen M. Janjigian, Yelena Healey, John H. Jarnagin, William R. Allen, Peter J. Sander, Chris Erdjument-Bromage, Hediye Neubert, Thomas A. Leach, Steven D. Chiosis, Gabriela Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer |
title | Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer |
title_full | Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer |
title_fullStr | Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer |
title_full_unstemmed | Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer |
title_short | Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer |
title_sort | pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617294/ https://www.ncbi.nlm.nih.gov/pubmed/34824367 http://dx.doi.org/10.1038/s42003-021-02842-3 |
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