Switching Addictions Between HER2 and FGFR2 in HER2-positive Breast Tumor Cells: FGFR2 as a Potential Target for Salvage After Lapatinib Failure

Biochem Biophys Res Commun. 2011 Apr 1;407(1):219-24. doi: 10.1016/j.bbrc.2011.03.002. Epub 2011 Mar 4.

Abstract

Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC(50) of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.

MeSH terms

  • Aged
  • Antineoplastic Agents / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / mortality
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Amplification
  • Humans
  • Lapatinib
  • Middle Aged
  • Protein Kinase Inhibitors / therapeutic use*
  • Quinazolines / therapeutic use*
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors*
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics
  • Salvage Therapy / methods*
  • Treatment Failure

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Quinazolines
  • Lapatinib
  • FGFR2 protein, human
  • Receptor, ErbB-2
  • Receptor, Fibroblast Growth Factor, Type 2