Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Breast Neoplasms
/ drug therapy
Cancer-Associated Fibroblasts
/ metabolism
Cell Line, Tumor
Drug Resistance, Neoplasm
Female
Humans
Lapatinib
/ administration & dosage
Mice
Mice, Nude
Neoplasm Recurrence, Local
/ drug therapy
Receptor, ErbB-2
/ antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 2
/ metabolism
Signal Transduction
Survival Rate
Trastuzumab
/ administration & dosage
Xenograft Model Antitumor Assays
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 03 2020
15 03 2020
Historique:
received:
26
02
2019
revised:
15
09
2019
accepted:
04
11
2019
pubmed:
9
11
2019
medline:
15
1
2021
entrez:
9
11
2019
Statut:
ppublish
Résumé
Despite the therapeutic success of existing HER2-targeted therapies, tumors invariably relapse. This study aimed at identifying new mechanisms responsible for HER2-targeted therapy resistance. We have used a platform of HER2-targeted therapy-resistant cell lines and primary cultures of healthy and tumor-associated fibroblasts (TAF) to identify new potential targets related to tumor escape from anti-HER2 therapies. We have shown that TAFs promote resistance to HER2-targeted therapies. TAFs produce and secrete high levels of FGF5, which induces FGFR2 activation in the surrounding breast cancer cells. FGFR2 transactivates HER2 via c-Src, leading to resistance to HER2-targeted therapies. We have identified the TAF/FGF5/FGFR2/c-Src/HER2 axis as an escape pathway responsible for HER2-targeted therapy resistance in breast cancer, which can be reversed by FGFR inhibitors.
Identifiants
pubmed: 31699826
pii: 1078-0432.CCR-19-0353
doi: 10.1158/1078-0432.CCR-19-0353
doi:
Substances chimiques
Lapatinib
0VUA21238F
ERBB2 protein, human
EC 2.7.10.1
FGFR2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 2
EC 2.7.10.1
Trastuzumab
P188ANX8CK
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1432-1448Informations de copyright
©2019 American Association for Cancer Research.