Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling.
Overexpression of the epidermal growth factor receptor (EGFR) has been shown previously to correlate with enhanced malignant potential of many human tumor types, including glioblastoma multiforme (GBM). Anti-EGFR targeting has been demonstrated to enhance apoptosis and reduce both cellular invasion and angiogenic potential. It remains unclear whether absolute EGFR expression levels are sufficient to predict which tumors will respond best to anti-EGFR therapy. We have identified two primary GBM cell lines with equivalent EGFR expression levels with very different sensitivities to the EGFR receptor tyrosine kinase inhibitor, AG1478. This was apparent despite similar reductions in EGFR signaling in both cell lines, as measured by phospho-EGFR levels. AG1478 enhanced both spontaneous and radiation-induced apoptosis and reduced invasive potential in the GBM(S), but not in the GBM(R), cell line. The resistant GBM(R) cell line demonstrated an up-regulation of insulin-like growth factor receptor I (IGFR-I) levels on AG1478 administration. This resulted in sustained signaling through the phosphoinositide 3-kinase pathway, resulting in potent antiapoptotic and proinvasion effects. Cotargeting IGFR-I with EGFR greatly enhanced both spontaneous and radiation-induced apoptosis of the GBM(R) cells and reduced their invasive potential. Akt1 and p70(s6k) appeared to be important downstream targets of IGFR-I-mediated resistance to anti-EGFR targeting. These findings suggest that IGFR-I signaling through phosphoinositide 3-kinase may represent a novel and potentially important mechanism of resistance to anti-EGFR therapy.
Chakravarti
Arnab
A
Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Charlestown, Massachusetts 02129, USA. achakravarti@partners.org
Loeffler
Jay S
JS
Dyson
Nicholas J
NJ
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D029681:Arabidopsis Proteins; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D010940:Plant Proteins / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D011799:Quinazolines; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology
D029681:Arabidopsis Proteins; D004791:Enzyme Inhibitors; D010940:Plant Proteins; D015221:Potassium Channels; D011799:Quinazolines; D020032:Tyrphostins; C074500:AKT1 protein, Arabidopsis; C101044:RTKI cpd; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D019893:Ribosomal Protein S6 Kinases