Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer release_glkj57arjfdz7fu5jmii43xurm

by Shailendra K. Gautam, Ranjana K. Kanchan, Jawed Siddiqui, Shailendra K. Maurya, Sanchita Rauth, Naveenkumar Perumal, Pranita Atri, Ramakanth C. Venkata, Kavita Mallya, Sameer Mirza, Moorthy Palanimuthu Ponnusamy, Vimla Band (+4 others)

Published in Cancers by MDPI AG.

2020   Volume 12, Issue 10, p2838

Abstract

Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2+) breast cancer (BC) patients. We proposed here that a combination treatment of irreversible tyrosine kinase inhibitor neratinib (NER) and the c-MET inhibitor cabozantinib (CBZ) could prevent brain metastasis. To address this, we first tested the combination treatment of NER and CBZ in the brain-seeking ERBB2+ cell lines SKBrM3 and JIMT-1-BR3, and in ERBB2+ organoids that expressed the c-MET/ERBB1 axis. Next, we developed and characterized an orthotopic mouse model of spontaneous BrM and evaluated the therapeutic effect of CBZ and NER in vivo. The combination treatment of NER and CBZ significantly inhibited proliferation and migration in ERBB2+ cell lines and reduced the organoid growth in vitro. Mechanistically, the combination treatment of NER and CBZ substantially inhibited ERK activation downstream of the c-MET/ERBB1 axis. Orthotopically implanted SKBrM3+ cells formed primary tumor in the mammary fat pad and spontaneously metastasized to the brain and other distant organs. Combination treatment with NER and CBZ inhibited primary tumor growth and predominantly prevented BrM. In conclusion, the orthotopic model of spontaneous BrM is clinically relevant, and the combination therapy of NER and CBZ might be a useful approach to prevent BrM in BC.
In application/xml+jats format

Archived Files and Locations

application/pdf  6.6 MB
file_ymmebhi37fesbmdybqlhbif5ca
web.archive.org (webarchive)
digitalcommons.unmc.edu (web)
application/pdf  4.2 MB
file_b32n43jnyvewlk7ejfhh44exw4
web.archive.org (webarchive)
res.mdpi.com (publisher)
Read Archived PDF
Archived
Type  article-journal
Stage   published
Date   2020-10-01
Language   en ?
Container Metadata
Open Access Publication
In DOAJ
In ISSN ROAD
In Keepers Registery
ISSN-L:  2072-6694
Work Entity
access all versions, variants, and formats of this works (eg, pre-prints)
Catalog Record
Revision: 3a35fd05-f4b5-4ee1-be4b-6219ea5441b2
API URL: JSON