ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer

Katharina Feldinger; Daniele Generali; Gabriela Kramer-Marek; Merel Gijsen; T B Ng; Jack Ho Wong; Carla Strina; Mariarosa Cappelletti; Daniele Andreis; Ji-Liang Li; Esther Bridges; Helen Turley; Russell Leek; Ioannis Roxanis; Jacek Capala; Gillian Murphy; Adrian L Harris; Anthony Kong

doi:10.18632/oncotarget.1955

ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer

Katharina Feldinger, Daniele Generali, Gabriela Kramer-Marek, Merel Gijsen, T B Ng, Jack Ho Wong, Carla Strina, Mariarosa Cappelletti, Daniele Andreis, Ji-Liang Li, Esther Bridges, Helen Turley, Russell Leek, Ioannis Roxanis, Jacek Capala, Gillian Murphy, Adrian L Harris, Anthony Kong

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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Abstract

Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p ≤ 0.001 in BT474; p ≤ 0.01 in SKBR3) and in vivo (p ≤ 0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p ≤ 0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p ≤ 0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p ≤ 0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients.

Original language	English
Pages (from-to)	6633-6646
Number of pages	14
Journal	OncoTarget
Volume	5
Issue number	16
Early online date	8 May 2014
DOIs	https://doi.org/10.18632/oncotarget.1955
Publication status	Published - Aug 2014

Keywords

ADAM Proteins
Amyloid Precursor Protein Secretases
Animals
Antibodies, Monoclonal, Humanized
Antineoplastic Agents
Breast Neoplasms
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm
Female
Gene Knockdown Techniques
Humans
Membrane Proteins
Mice
Receptor, ErbB-2
Xenograft Model Antitumor Assays
Trastuzumab
resistance
ADAM10
HER2
survival

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Feldinger, K., Generali, D., Kramer-Marek, G., Gijsen, M., Ng, T. B., Wong, J. H., Strina, C., Cappelletti, M., Andreis, D., Li, J.-L., Bridges, E., Turley, H., Leek, R., Roxanis, I., Capala, J., Murphy, G., Harris, A. L., & Kong, A. (2014). ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer. OncoTarget, 5(16), 6633-6646. https://doi.org/10.18632/oncotarget.1955

@article{8cb735498de1469e91ae73a4195b9951,

title = "ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer",

abstract = "Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p ≤ 0.001 in BT474; p ≤ 0.01 in SKBR3) and in vivo (p ≤ 0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in na{\"i}ve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p ≤ 0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p ≤ 0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p ≤ 0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients.",

keywords = "ADAM Proteins, Amyloid Precursor Protein Secretases, Animals, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Drug Resistance, Neoplasm, Female, Gene Knockdown Techniques, Humans, Membrane Proteins, Mice, Receptor, ErbB-2, Xenograft Model Antitumor Assays, Trastuzumab, resistance, ADAM10, HER2, survival",

author = "Katharina Feldinger and Daniele Generali and Gabriela Kramer-Marek and Merel Gijsen and Ng, {T B} and Wong, {Jack Ho} and Carla Strina and Mariarosa Cappelletti and Daniele Andreis and Ji-Liang Li and Esther Bridges and Helen Turley and Russell Leek and Ioannis Roxanis and Jacek Capala and Gillian Murphy and Harris, {Adrian L} and Anthony Kong",

year = "2014",

month = aug,

doi = "10.18632/oncotarget.1955",

language = "English",

volume = "5",

pages = "6633--6646",

journal = "OncoTarget",

issn = "1949-2553",

publisher = "Impact Journals",

number = "16",

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Feldinger, K, Generali, D, Kramer-Marek, G, Gijsen, M, Ng, TB, Wong, JH, Strina, C, Cappelletti, M, Andreis, D, Li, J-L, Bridges, E, Turley, H, Leek, R, Roxanis, I, Capala, J, Murphy, G, Harris, AL & Kong, A 2014, 'ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer', OncoTarget, vol. 5, no. 16, pp. 6633-6646. https://doi.org/10.18632/oncotarget.1955

TY - JOUR

T1 - ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer

AU - Feldinger, Katharina

AU - Generali, Daniele

AU - Kramer-Marek, Gabriela

AU - Gijsen, Merel

AU - Ng, T B

AU - Wong, Jack Ho

AU - Strina, Carla

AU - Cappelletti, Mariarosa

AU - Andreis, Daniele

AU - Li, Ji-Liang

AU - Bridges, Esther

AU - Turley, Helen

AU - Leek, Russell

AU - Roxanis, Ioannis

AU - Capala, Jacek

AU - Murphy, Gillian

AU - Harris, Adrian L

AU - Kong, Anthony

PY - 2014/8

Y1 - 2014/8

N2 - Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p ≤ 0.001 in BT474; p ≤ 0.01 in SKBR3) and in vivo (p ≤ 0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p ≤ 0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p ≤ 0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p ≤ 0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients.

AB - Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p ≤ 0.001 in BT474; p ≤ 0.01 in SKBR3) and in vivo (p ≤ 0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p ≤ 0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p ≤ 0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p ≤ 0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients.

KW - ADAM Proteins

KW - Amyloid Precursor Protein Secretases

KW - Animals

KW - Antibodies, Monoclonal, Humanized

KW - Antineoplastic Agents

KW - Breast Neoplasms

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Drug Resistance, Neoplasm

KW - Female

KW - Gene Knockdown Techniques

KW - Humans

KW - Membrane Proteins

KW - Mice

KW - Receptor, ErbB-2

KW - Xenograft Model Antitumor Assays

KW - Trastuzumab

KW - resistance

KW - ADAM10

KW - HER2

KW - survival

U2 - 10.18632/oncotarget.1955

DO - 10.18632/oncotarget.1955

M3 - Article

C2 - 24952873

SN - 1949-2553

VL - 5

SP - 6633

EP - 6646

JO - OncoTarget

JF - OncoTarget

IS - 16

ER -

ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer

Abstract

Keywords

UN SDGs

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