Data from Elevation of Receptor Tyrosine Kinase EphA2 Mediates Resistance to Trastuzumab Therapy

Authors:
  • GZGuanglei Zhuang
    Guanglei Zhuang
  • DBDana M. Brantley-Sieders
    Dana M. Brantley-Sieders
  • DVDavid Vaught
    David Vaught
  • JYJian Yu
    Jian Yu
  • LXLu Xie
    Lu Xie
  • SWSam Wells
    Sam Wells
  • DJDowdy Jackson
    Dowdy Jackson
  • RMRebecca Muraoka-Cook
    Rebecca Muraoka-Cook
  • CACarlos Arteaga
    Carlos Arteaga
  • JCJin Chen
    Jin Chen
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Abstract
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. Cancer Res; 70(1); 299–308.