Growth factor receptor interplay and resistance in cancer.
Aberrant signalling through the epidermal growth factor receptor (EGFR) plays a major role in the progression and maintenance of the malignant phenotype and the receptor is therefore a rational anti-cancer target. A variety of approaches have been developed to specifically target the EGFR which include monoclonal antibodies and small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa). However, the recent clinical experience across a range of cancer types is revealing that despite the anti-EGFR agents demonstrating some anti-tumour activity, there is a high level of de novo and acquired resistance to such treatments and moreover, overexpression of the EGFR is clearly not the sole determinant of response to such therapies. Such adverse phenomena, which serve to limit the overall therapeutic impact of these new agents, implies the existence of a greater complexity involved in the regulation of EGFR signalling than was previously assumed. Indeed, evidence is accumulating which demonstrates that signalling interplay occurs between the EGFR, and the IGF-1 receptor (IGF-1R) and the review will focus on the emerging concept of growth factor pathway switching between these two receptors as a means of influencing the effectiveness of anti-EGFR agents such as gefitinib.
Jones
Helen E
HE
Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Redwood Building, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK. joneshe1@cardiff.ac.uk
Gee
Julia M W
JM
Hutcheson
Iain R
IR
Knowlden
Janice M
JM
Barrow
Denise
D
Nicholson
Robert I
RI
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000077156:Gefitinib; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D011485:Protein Binding; D011799:Quinazolines / Q000627:therapeutic use; D020239:Receptor Cross-Talk / Q000187:drug effects*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D000077156:Gefitinib