Blocking c‐met/erbb1 axis prevents brain metastasis in erbb2+ breast cancer

Shailendra K. Gautam, Ranjana K. Kanchan, Jawed A. Siddiqui, Shailendra K. Maurya, Sanchita Rauth, Naveenkumar Perumal, Pranita Atri, Ramakanth C. Venkata, Kavita Mallya, Sameer Mirza, Moorthy P. Ponnusamy, Vimla Band, Sidharth Mahapatra, Maneesh Jain, Surinder K. Batra, Mohd Wasim Nasser

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number2838
Pages (from-to)1-20
Number of pages20
JournalCancers
Volume12
Issue number10
DOIs
StatePublished - Oct 2020

Keywords

  • Brain metastasis
  • Breast cancer
  • Cabozantinib
  • Combination therapy
  • C‐MET/ERBB1 axis
  • Neratinib
  • Organoids
  • Orthotopic model
  • Spontaneous metastasis
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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