Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers

Oncogene. 2017 Oct 5;36(40):5620-5630. doi: 10.1038/onc.2017.170. Epub 2017 Jun 5.

Abstract

Basal-like/triple-negative breast cancers (TNBCs) are among the most aggressive forms of breast cancer, and disproportionally affects young premenopausal women and women of African descent. Patients with TNBC suffer a poor prognosis due in part to a lack of molecularly targeted therapies, which represents a critical barrier for effective treatment. Here, we identify EphA2 receptor tyrosine kinase as a clinically relevant target for TNBC. EphA2 expression is enriched in the basal-like molecular subtype in human breast cancers. Loss of EphA2 function in both human and genetically engineered mouse models of TNBC reduced tumor growth in culture and in vivo. Mechanistically, targeting EphA2 impaired cell cycle progression through S-phase via downregulation of c-Myc and stabilization of the cyclin-dependent kinase inhibitor p27/KIP1. A small molecule kinase inhibitor of EphA2 effectively suppressed tumor cell growth in vivo, including TNBC patient-derived xenografts. Thus, our data identify EphA2 as a novel molecular target for TNBC.

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Cell Cycle*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Ephrin-A2 / antagonists & inhibitors
  • Ephrin-A2 / genetics
  • Ephrin-A2 / metabolism*
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Neoplasm Recurrence, Local
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-myb / metabolism
  • Receptor, EphA2
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / therapy
  • Xenograft Model Antitumor Assays

Substances

  • ALW-II-41-27
  • Benzamides
  • EPHA2 protein, human
  • Ephrin-A2
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-myb
  • Cyclin-Dependent Kinase Inhibitor p27
  • Niacinamide
  • Receptor, EphA2