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

被引：70

作者：

Feldinger, Katharina ^{[1
]}

Generali, Daniele ^{[3
]}

Kramer-Marek, Gabriela ^{[4
]}

Gijsen, Merel ^{[1
]}

Ng, Tzi Bun ^{[5
]}

Wong, Jack Ho ^{[5
]}

Strina, Carla ^{[3
]}

Cappelletti, Mariarosa ^{[3
]}

Andreis, Daniele ^{[3
]}

Li, Ji-Liang ^{[2
]}

Bridges, Esther ^{[2
]}

Turley, Helen ^{[2
]}

Leek, Russell ^{[2
]}

Roxanis, Ioannis ^{[6
,7
]}

Capala, Jacek ^{[4
]}

Murphy, Gillian ^{[8
]}

Harris, Adrian L. ^{[2
]}

Kong, Anthony ^{[1
]}

机构：

[1] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Human Epidermal Growth Factor Grp,Dept Oncol, Oxford OX3 9DU, England

[2] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Growth Factor Grp,Dept Oncol, Oxford OX3 9DU, England

[3] AO Inst Ospitalieri Cremona, US Terapia Mol & Farmacogenom, UO Multidisciplinare Patol Mammaria, Cremona, Italy

[4] NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA

[5] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China

[6] Oxford Univ Hosp, Dept Cellular Pathol, Oxford, England

[7] Oxford Biomed Res Ctr, Oxford, England

[8] Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Cambridge, England

来源：

ONCOTARGET | 2014年 / 5卷 / 16期

基金：

美国国家卫生研究院;

关键词：

Trastuzumab; resistance; ADAM10; HER2; survival; EPIDERMAL-GROWTH-FACTOR; CELL-CELL ADHESION; ADJUVANT CHEMOTHERAPY; MONOCLONAL-ANTIBODY; FACTOR RECEPTOR; ACTIVATION; EXPRESSION; INHIBITION; EFFICACY; CLEAVAGE;

D O I：

10.18632/oncotarget.1955

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 naive 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.

引用

页码：6633 / 6646

页数：14

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