Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
25 11 2021
25 11 2021
Historique:
received:
29
01
2021
accepted:
03
11
2021
entrez:
26
11
2021
pubmed:
27
11
2021
medline:
15
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34824367
doi: 10.1038/s42003-021-02842-3
pii: 10.1038/s42003-021-02842-3
pmc: PMC8617294
doi:
Substances chimiques
Molecular Chaperones
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1333Subventions
Organisme : NIA NIH HHS
ID : R56 AG061869
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA155226
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA192937
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG072599
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG074004
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172546
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR027990
Pays : United States
Organisme : NIH HHS
ID : U54 OD020355
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG067598
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG028811
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA186866
Pays : United States
Informations de copyright
© 2021. The Author(s).
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