TY - JOUR
T1 - Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy
AU - Zhuang, Guanglei
AU - Brantley-Sieders, Dana M.
AU - Vaught, David
AU - Yu, Jian
AU - Xie, Lu
AU - Wells, Sam
AU - Jackson, Dowdy
AU - Muraoka-Cook, Rebecca
AU - Arteaga, Carlos
AU - Chen, Jin
PY - 2010/1/1
Y1 - 2010/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=75149129568&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=75149129568&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-09-1845
DO - 10.1158/0008-5472.CAN-09-1845
M3 - Article
C2 - 20028874
AN - SCOPUS:75149129568
SN - 0008-5472
VL - 70
SP - 299
EP - 308
JO - Cancer research
JF - Cancer research
IS - 1
ER -