Reversing MET-Mediated Resistance in Oncogene-Driven NSCLC by MET-Activated Wnt Condensative Prodrug.
MET amplification
NSCLC
Wnt inhibitor
drug development
peptide
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569
Informations de publication
Date de publication:
13 Jun 2024
13 Jun 2024
Historique:
revised:
10
05
2024
received:
16
01
2024
medline:
13
6
2024
pubmed:
13
6
2024
entrez:
13
6
2024
Statut:
aheadofprint
Résumé
The amplification of MET is a major cause of acquired resistance to targeted therapy in EGFR-mutant non-small-cell lung cancer (NSCLC), only to be temporarily restrained by the partial efficacy of MET inhibitors. This study reveals that the MET inhibitor has unexpectedly limited efficacy due to amplified MET triggering a strong positive feedback loop in the Wnt/β-catenin signaling pathway, allowing optimal functionality even when the MET pathway is suppressed again. To test this conjecture and specifically target the Wnt/β-catenin pathway, a cleverly designed Wnt condensative pro drug called WntSI is developed using reversible supramolecular self-assembly driven by liquidliquid phase separation (LLPS). This process involves a MET/pH-responsive peptide (Tyr-Pep) and a potent Wnt inhibitor known as CA. Upon recognition and phosphorylation of Tyr-Pep by over expressed MET in cells, it disrupts LLPS propensity and facilitates the disintegration of WntSI. Consequently,this enables it to suppress the carcinogenic effect mediated by β-catenin,effectively overcoming acquired resistance to EGFR-TKIs caused by MET amplification in both cell line-derived and patient-derived tumor xenograft (PDX) mouse models while maintaining exceptional biosecurity. This effective strategy not only suppresses the Wnt/β-catenin signaling pathway selectively, but also serves as an innovative example for pro-drug development through biologically responsive LLPS.
Identifiants
pubmed: 38867713
doi: 10.1002/advs.202400603
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2400603Subventions
Organisme : National Key Research and Development Program of China
ID : 2022YFE0133500
Organisme : National Natural Science Foundation of China
ID : 22007076
Organisme : National Natural Science Foundation of China
ID : 82272782
Organisme : National Natural Science Foundation of China
ID : 32171256
Organisme : National Natural Science Foundation of China
ID : 82141126
Informations de copyright
© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.
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