RON confers lapatinib resistance in HER2-positive breast cancer cells

Cancer Lett. 2013 Oct 28;340(1):43-50. doi: 10.1016/j.canlet.2013.06.022. Epub 2013 Jun 27.

Abstract

Lapatinib-resistance is a major problem for HER2-positive breast cancer treatment. SK-BR-3-LR, a lapatinib-resistant cell clone, was established from HER2-positive SK-BR-3 breast cancer cells following chronic exposure to lapatinib. The PI3K/AKT signaling pathway was demonstrated to be resistant to HER2 inhibition in SK-BR-3-LR cells. However, both small-molecular Recepteur d'Origine Nantais (RON) inhibitors and RON-targeted small interfering RNA (siRNA) effectively restored lapatinib sensitivity in these cells by inhibiting PI3K/AKT activation. Our results demonstrate for the first time the important role of RON in mediating lapatinib resistance and suggest that RON-targeted therapy may become a novel, promising therapeutic strategy after the failure of lapatinib treatment in patients with HER2-positive breast cancer.

Keywords: HER2; HER2-targeted agents; Lapatinib resistance; RON.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crizotinib
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Inhibitory Concentration 50
  • Lapatinib
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Quinazolines / pharmacology*
  • Quinolines / pharmacology
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, ErbB-2 / metabolism*
  • Signal Transduction
  • Trastuzumab

Substances

  • Anilides
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • GSK 1363089
  • Pyrazoles
  • Pyridines
  • Quinazolines
  • Quinolines
  • Lapatinib
  • Crizotinib
  • Phosphatidylinositol 3-Kinases
  • ERBB2 protein, human
  • RON protein
  • Receptor Protein-Tyrosine Kinases
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-akt
  • Trastuzumab