Rebecca Cook
Faculty Member
Last active: 4/15/2019

Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy.

Zhuang G, Brantley-Sieders DM, Vaught D, Yu J, Xie L, Wells S, Jackson D, Muraoka-Cook R, Arteaga C, Chen J
Cancer Res. 2010 70 (1): 299-308

PMID: 20028874 · PMCID: PMC3859619 · 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.

MeSH Terms (19)

Animals Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Antineoplastic Agents Blotting, Western Breast Neoplasms Cell Line, Tumor Drug Resistance, Neoplasm Female Humans Mice Mice, Nude Receptor, EphA2 Receptor, ErbB-2 Signal Transduction src-Family Kinases Survival Analysis Trastuzumab Xenograft Model Antitumor Assays

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