The plasticity of oncogene addiction: Implications for targeted therapies directed to receptor tyrosine kinases.

Vinochani Pillay, Layal Allaf, Alex L Wilding, jacqui f donoghue, Naomi W Court, Sameer Greenall, Andrew M Scott and Terrance G Johns

Year 2009, Volume 11, Issue 5

Abstract

A common mutation of the epidermal growth factor receptor (EGFR) in glioblastoma multiforme (GBM) is an extracellular truncation known as the de2-7 EGFR (or EGFRvIII). Hepatocyte growth factor (HGF) is the ligand for the receptor tyrosine kinase (RTK) c-Met and this signalling axis is often active in GBM. Expression of the HGF/c-Met axis or de2-7 EGFR independently enhances GBM growth and invasiveness, particularly through the PI(3)K/pAkt pathway. Using RTK arrays, we show that expression of de2-7 EGFR in U87MG GBM cells leads to co-activation of several RTKs, including PDGFRâ and c-Met. A neutralizing antibody to HGF (AMG 102) did not inhibit de2-7 EGFR mediated activation of c-Met, demonstrating that it is ligand independent. Therapy of parental U87MG xenografts with AMG 102 resulted in significant inhibition of tumor growth, while U87MG.Ä2-7 xenografts were profoundly resistant to therapy. Treatment of U87MG.Ä2-7 xenografts with Panitumumab, an anti-EGFR antibody, only partially inhibited tumor growth as xenografts rapidly reverted to the HGF/c-Met signalling pathway. Co-treatment with Panitumumab and AMG 102 prevented this escape leading to significant tumor inhibition via an apoptotic mechanism; an observation consistent with the induction of oncogenic shock. This observation provides a rationale for using Panitumumab and AMG 102 in combination for the treatment of GBM patients. These results illustrate that GBM cells can rapidly change the RTK driving their oncogene addiction if the alternate RTK signals through the same downstream pathway. Consequently, inhibition of a dominant oncogene by targeted therapy can alter the hierarchy of RTKs resulting in rapid therapeutic resistance.

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