Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer
Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2<sup>+</sup>) breast cancer (BC) patients. We proposed here that a combination treatment of irreversible tyrosine kinase inhibitor neratinib (NER) and the c...
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2020-10-01
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doaj-dc3db0c586f144d1ab089750af98dc392020-11-25T03:51:27ZengMDPI AGCancers2072-66942020-10-01122838283810.3390/cancers12102838Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast CancerShailendra K. Gautam0Ranjana K. Kanchan1Jawed A. Siddiqui2Shailendra K. Maurya3Sanchita Rauth4Naveenkumar Perumal5Pranita Atri6Ramakanth C. Venkata7Kavita Mallya8Sameer Mirza9Moorthy P. Ponnusamy10Vimla Band11Sidharth Mahapatra12Maneesh Jain13Surinder K. Batra14Mohd Wasim Nasser15Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USABrain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2<sup>+</sup>) 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<sup>+</sup> cell lines SKBrM3 and JIMT-1-BR3, and in ERBB2<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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.https://www.mdpi.com/2072-6694/12/10/2838breast cancerbrain metastasistargeted therapyc-MET/ERBB1 axiscombination therapyorthotopic model |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer Cancers breast cancer brain metastasis targeted therapy c-MET/ERBB1 axis combination therapy orthotopic model |
author_facet |
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 |
author_sort |
Shailendra K. Gautam |
title |
Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer |
title_short |
Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer |
title_full |
Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer |
title_fullStr |
Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer |
title_full_unstemmed |
Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer |
title_sort |
blocking c-met/erbb1 axis prevents brain metastasis in erbb2+ breast cancer |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-10-01 |
description |
Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2<sup>+</sup>) 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<sup>+</sup> cell lines SKBrM3 and JIMT-1-BR3, and in ERBB2<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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. |
topic |
breast cancer brain metastasis targeted therapy c-MET/ERBB1 axis combination therapy orthotopic model |
url |
https://www.mdpi.com/2072-6694/12/10/2838 |
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