The Plasticity of Oncogene Addiction: Implications for Targeted Therapies Directed to Receptor Tyrosine Kinases

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 signaling axis is often active in GBM. The expression of the HGF/c-Met axis or de2-7 EGFR independently enhances GBM growth and invasiveness, particularly through the phosphatidylinositol-3 kinase/pAkt pathway. Using RTK arrays, we show that expression of de2-7 EGFR in U87MG GBM cells leads to the coactivation of several RTKs, including platelet-derived growth factor receptor beta and c-Met. A neutralizing antibody to HGF (AMG102) did not inhibit de2-7 EGFR-mediated activation of c-Met, demonstrating that it is ligand-independent. Therapy for parental U87MG xenografts with AMG 102 resulted in significant inhibition of tumor growth, whereas U87MG.Delta 2-7 xenografts were profoundly resistant. Treatment of U87MG.Delta 2-7 xenografts with panitumumab, an anti-EGFR antibody, only partially inhibited tumor growth as xenografts rapidly reverted to the HGF/c-Met signaling pathway. Cotreatment with panitumumab and AMG 102 prevented this escape leading to significant tumor inhibition through an apoptotic mechanism, 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.

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

“…[10][11][12] Hepatocyte Growth Factor (HGF) and its receptor c-Met are both overexpressed in GBM, contributing to tumor growth invasion, angiogenesis and conferring a stem-like phenotype and poor prognosis. 10,[13][14][15][16] Although activating mutations of b-catenin have not been identified in GBM 17 , overexpression of b-catenin and other Wnt pathway components (including Fz 18 ) together with epigenetic regulation of Wnt inhibitors results in Wnt/ b-catenin activation in GBM. [19][20][21] Overexpression of the Forkhead box M1 (FoxM1) transcription factor represents a critical mechanism further contributing to b-catenin signaling in GBM.…”

In Situ Analysis of Mutant EGFRs Prevalent in Glioblastoma Multiforme Reveals Aberrant Dimerization, Activation, and Differential Response to Anti-EGFR Targeted Therapy

“…Recent reports have suggested that EGFR dimerization has an important role in sustaining a tumorigenic state in GBMs and evading EGFR-targeted therapies (8). Inhibitors that selectively impair dimerization of EGFRs are hence of potential interest requiring understanding of the intricacies of EGFR dimerization, specifically the interaction capacity of EGFR mutants that are relevant in the context of GBMs.…”

Advances in the Development of EGFR Targeted Therapies for the Treatment of Glioblastoma

“…We recently showed that co-expression of de2-7 EGFR and c-Met in GBM xenografts causes therapeutic resistant to single agents directed to either of these RTK. However, the combination of EGFR and c-Met inhibitors produced synergistic anti-tumor activity (Pillay et al, 2009), confirming that dual inhibition of RTKs is a valid approach in GBM. A number of other RTKs have been shown to be activated in GBM including the FGFR family, Axl, ErbB2/3/4, EphA2/7, VEGFR2 and PDGFR / (Ren et al, 2007;Pillay et al, 2009).…”

“…However, the combination of EGFR and c-Met inhibitors produced synergistic anti-tumor activity (Pillay et al, 2009), confirming that dual inhibition of RTKs is a valid approach in GBM. A number of other RTKs have been shown to be activated in GBM including the FGFR family, Axl, ErbB2/3/4, EphA2/7, VEGFR2 and PDGFR / (Ren et al, 2007;Pillay et al, 2009). Given the range of potential RTKs activated in a given patient, the most effective therapeutic strategy may have to be determined by screening patient tissues for RTK mutation and/or activation (i.e.…”