Inhibition of epidermal growth factor receptor signalling reduces hypercalcaemia induced by human lung squamous-cell carcinoma in athymic mice

Br J Cancer. 2007 Jul 16;97(2):183-93. doi: 10.1038/sj.bjc.6603828. Epub 2007 May 29.


The purpose of this study was to evaluate the role of the epidermal growth factor receptor (EGFR) in parathyroid hormone-related protein (PTHrP) expression and humoral hypercalcaemia of malignancy (HHM), using two different human squamous-cell carcinoma (SCC) xenograft models. A randomised controlled study in which nude mice with RWGT2 and HARA xenografts received either placebo or gefitinib 200 mg kg(-1) for 3 days after developing HHM. Effectiveness of therapy was evaluated by measuring plasma calcium and PTHrP, urine cyclic AMP/creatinine ratios, and tumour volumes. The study end point was at 78 h. The lung SCC lines, RWGT2 and HARA, expressed high levels of PTHrP mRNA as well as abundant EGFR protein, but very little erbB2 or erbB3. Both lines expressed high transcript levels for the EGFR ligand, amphiregulin (AREG), as well as, substantially lower levels of transforming growth factor-alpha (TGF-alpha), and heparin binding-epidermal growth factor (HB-EGF) mRNA. Parathyroid hormone-related protein gene expression in both lines was reduced 40-80% after treatment with 1 muM of EGFR tyrosine kinase inhibitor PD153035 and precipitating antibodies to AREG. Gefitinib treatment of hypercalcaemic mice with RWGT2 and HARA xenografts resulted in a significant reduction of plasma total calcium concentrations by 78 h. Autocrine AREG stimulated the EGFR and increased PTHrP gene expression in the RWGT2 and HARA lung SCC lines. Inhibition of the EGFR pathway in two human SCC models of HHM by an anilinoquinazoline demonstrated that the EGFR tyrosine kinase is a potential target for antihypercalcaemic therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphiregulin
  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Squamous Cell / complications*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • EGF Family of Proteins
  • ErbB Receptors / analysis
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Gefitinib
  • Gene Expression Regulation, Neoplastic*
  • Glycoproteins / analysis
  • Glycoproteins / metabolism
  • Humans
  • Hypercalcemia / drug therapy*
  • Hypercalcemia / etiology
  • Hypercalcemia / genetics
  • Intercellular Signaling Peptides and Proteins / analysis
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lung Neoplasms / complications*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Parathyroid Hormone-Related Protein / genetics*
  • Quinazolines / therapeutic use*
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Receptor, ErbB-2 / analysis
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Receptor, ErbB-3 / analysis
  • Receptor, ErbB-3 / genetics
  • Receptor, ErbB-3 / metabolism
  • Signal Transduction
  • Xenograft Model Antitumor Assays


  • AREG protein, human
  • Amphiregulin
  • Antineoplastic Agents
  • Areg protein, mouse
  • EGF Family of Proteins
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Parathyroid Hormone-Related Protein
  • Quinazolines
  • RNA, Messenger
  • ErbB Receptors
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Mitogen-Activated Protein Kinase Kinases
  • Gefitinib