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

doi:10.3390/cancers12102838

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 journal › Article › peer-review

5 Scopus citations

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 language	English (US)
Article number	2838
Pages (from-to)	1-20
Number of pages	20
Journal	Cancers
Volume	12
Issue number	10
DOIs	https://doi.org/10.3390/cancers12102838
State	Published - 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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10.3390/cancers12102838

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Gautam, S. K., Kanchan, R. K., Siddiqui, J. A., Maurya, S. K., Rauth, S., Perumal, N., Atri, P., Venkata, R. C., Mallya, K., Mirza, S., Ponnusamy, M. P., Band, V., Mahapatra, S., Jain, M., Batra, S. K., & Nasser, M. W. (2020). Blocking c‐met/erbb1 axis prevents brain metastasis in erbb2+ breast cancer. Cancers, 12(10), 1-20. Article 2838. https://doi.org/10.3390/cancers12102838

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title = "Blocking c‐met/erbb1 axis prevents brain metastasis in erbb2+ breast cancer",

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.",

keywords = "Brain metastasis, Breast cancer, Cabozantinib, Combination therapy, C‐MET/ERBB1 axis, Neratinib, Organoids, Orthotopic model, Spontaneous metastasis, Targeted therapy",

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

note = "Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = oct,

doi = "10.3390/cancers12102838",

language = "English (US)",

volume = "12",

pages = "1--20",

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T1 - Blocking c‐met/erbb1 axis prevents brain metastasis in erbb2+ breast cancer

AU - Gautam, Shailendra K.

AU - Kanchan, Ranjana K.

AU - Siddiqui, Jawed A.

AU - Maurya, Shailendra K.

AU - Rauth, Sanchita

AU - Perumal, Naveenkumar

AU - Atri, Pranita

AU - Venkata, Ramakanth C.

AU - Mallya, Kavita

AU - Mirza, Sameer

AU - Ponnusamy, Moorthy P.

AU - Band, Vimla

AU - Mahapatra, Sidharth

AU - Jain, Maneesh

AU - Batra, Surinder K.

AU - Nasser, Mohd Wasim

PY - 2020/10

Y1 - 2020/10

N2 - 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.

AB - 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.

KW - Brain metastasis

KW - Breast cancer

KW - Cabozantinib

KW - Combination therapy

KW - C‐MET/ERBB1 axis

KW - Neratinib

KW - Organoids

KW - Orthotopic model

KW - Spontaneous metastasis

KW - Targeted therapy

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U2 - 10.3390/cancers12102838

DO - 10.3390/cancers12102838

M3 - Article

C2 - 33019652

AN - SCOPUS:85091975774

SN - 2072-6694

VL - 12

SP - 1

EP - 20

JO - Cancers

JF - Cancers

IS - 10

M1 - 2838

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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