Elevation of Receptor Tyrosine Kinase EphA2 Mediates Resistance to Trastuzumab Therapy

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 1; pp. 299 - 308
• Main Authors: GUANGLEI ZHUANG, BRANTLEY-SIEDERS, Dana M, VAUGHT, David, JIAN YU, LU XIE, WELLS, Sam, JACKSON, Dowdy, MURAOKA-COOK, Rebecca, ARTEAGA, Carlos, JIN CHEN
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.01.2010
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Blotting, Western; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Cell Line, Tumor; Drug Resistance, Neoplasm - genetics; Female; Humans; Medical sciences; Mice; Mice, Nude; Pharmacology. Drug treatments; Receptor, EphA2 - biosynthesis; Receptor, EphA2 - genetics; Receptor, ErbB-2 - biosynthesis; Receptor, ErbB-2 - genetics; Signal Transduction - drug effects; src-Family Kinases - drug effects; src-Family Kinases - metabolism; Survival Analysis; Trastuzumab; Tumors; Xenograft Model Antitumor Assays; Antineoplastic agent; Resistance; trk receptor; Treatment; Monoclonal antibody; Trastuzumab
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-09-1845

One arising challenge in the treatment of breast cancer is the development of therapeutic resistance to trastuzumab, an antibody targeting the human epidermal growth factor receptor-2 (HER2), which is frequently amplified in breast cancers. In this study, we provide evidence that elevated level of the receptor tyrosine kinase Eph receptor A2 (EphA2) is an important contributor to trastuzumab resistance. In a screen of a large cohort of human breast cancers, we found that EphA2 overexpression correlated with a decrease in disease-free and overall survival of HER2-overexpressing patients. Trastuzumab-resistant cell lines overexpressed EphA2, whereas inhibiting EphA2 restored sensitivity to trastuzumab treatment in vivo. Notably, trastuzumab treatment could promote EphA2 phosphorylation by activating Src kinase, leading in turn to an amplification of phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase signaling in resistant cells. Our findings offer mechanistic insights into the basis for trastuzumab resistance and rationalize strategies to target EphA2 as a tactic to reverse trastuzumab resistance.