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

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

doi:10.18632/oncotarget.1955

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.

Highlights

The HER family of receptor tyrosine kinases includes four receptors: EGFR, HER2, HER3, and HER4
Since ADAM17 and ADAM10 are the two best characterized ADAM proteases responsible for HER ligand shedding [14], we investigated the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cell lines, in vivo and in HER2 positive breast cancer patients
We showed that the upregulation of ADAM10 levels occurred during trastuzumab treatment and upon acquired resistance in HER2 positive breast cancer cells

Summary

INTRODUCTION

The HER (human epidermal growth factor receptor) family of receptor tyrosine kinases includes four receptors: EGFR, HER2, HER3, and HER4. Several ligands bind to these receptors including heregulin and betacellulin [1]. Trastuzumab (Herceptin), a humanized monoclonal antibody recognizing HER2 [7, 8], is effective in the treatment of HER2 overexpressing breast cancer in adjuvant and metastatic settings [9,10,11,12]. The role of ADAM10 overexpression was reported in several malignancies such as gastric [21], prostate [22], and liver [23] its clinical significance in breast cancer is unknown. Since ADAM17 and ADAM10 are the two best characterized ADAM proteases responsible for HER ligand shedding [14], we investigated the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cell lines, in vivo and in HER2 positive breast cancer patients

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS