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

G. Lorch, J. L. Gilmore, P. F. Koltz, R. M. Gonterman, R. Laughner, D. A. Lewis, Raymond Konger, K. S. Nadella, R. E. Toribio, T. J. Rosol, John Foley

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Abstract

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-α (TGF-α), 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 μM 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.

Original languageEnglish
Pages (from-to)183-193
Number of pages11
JournalBritish Journal of Cancer
Volume97
Issue number2
DOIs
StatePublished - Jul 10 2007

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Hypercalcemia
Epidermal Growth Factor Receptor
Nude Mice
Parathyroid Hormone-Related Protein
Squamous Cell Carcinoma
Lung
Heterografts
Protein-Tyrosine Kinases
Calcium
Gene Expression
Cell Line
Messenger RNA
Transforming Growth Factors
Therapeutics
Tumor Burden
Epidermal Growth Factor
Cyclic AMP
Heparin
Creatinine
Placebos

Keywords

  • Anilinoquinazolines
  • Gefitinib
  • Hypercalcaemia
  • Lung cancer
  • PTHrP
  • ZD1839

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibition of epidermal growth factor receptor signalling reduces hypercalcaemia induced by human lung squamous-cell carcinoma in athymic mice. / Lorch, G.; Gilmore, J. L.; Koltz, P. F.; Gonterman, R. M.; Laughner, R.; Lewis, D. A.; Konger, Raymond; Nadella, K. S.; Toribio, R. E.; Rosol, T. J.; Foley, John.

In: British Journal of Cancer, Vol. 97, No. 2, 10.07.2007, p. 183-193.

Research output: Contribution to journalArticle

Lorch, G. ; Gilmore, J. L. ; Koltz, P. F. ; Gonterman, R. M. ; Laughner, R. ; Lewis, D. A. ; Konger, Raymond ; Nadella, K. S. ; Toribio, R. E. ; Rosol, T. J. ; Foley, John. / Inhibition of epidermal growth factor receptor signalling reduces hypercalcaemia induced by human lung squamous-cell carcinoma in athymic mice. In: British Journal of Cancer. 2007 ; Vol. 97, No. 2. pp. 183-193.
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