Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer Journal Article


Authors: Joshi, S.; Gomes, E. D.; Wang, T.; Corben, A.; Taldone, T.; Gandu, S.; Xu, C.; Sharma, S.; Buddaseth, S.; Yan, P.; Chan, L. Y. L.; Gokce, A.; Rajasekhar, V. K.; Shrestha, L.; Panchal, P.; Almodovar, J.; Digwal, C. S.; Rodina, A.; Merugu, S.; Pillarsetty, N. V. K.; Miclea, V.; Peter, R. I.; Wang, W.; Ginsberg, S. D.; Tang, L.; Mattar, M.; de Stanchina, E.; Yu, K. H.; Lowery, M.; Grbovic-Huezo, O.; O’Reilly, E. M.; Janjigian, Y.; Healey, J. H.; Jarnagin, W. R.; Allen, P. J.; Sander, C.; Erdjument-Bromage, H.; Neubert, T. A.; Leach, S. D.; Chiosis, G.
Article Title: Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer
Abstract: 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. © 2021, The Author(s).
Journal Title: Communications Biology
Volume: 4
ISSN: 2399-3642
Publisher: Springer Nature  
Date Published: 2021-11-25
Start Page: 1333
Language: English
DOI: 10.1038/s42003-021-02842-3
PROVIDER: scopus
PMCID: PMC8617294
PUBMED: 34824367
DOI/URL:
Notes: Article -- MSK authors Gokce Askan's first and last names are reversed on the original publication -- MSK authors Liza Shrestha's first names is misspelled on the original publication -- Export Date: 3 January 2022 -- Source: Scopus
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