Receptor tyrosine kinase (RTK) systems, such as
hepatocyte growth factor (HGF) and its receptor c-Met, and
epidermal growth factor receptor (EGFR), are responsible for the malignant progression of multiple solid
tumors. Recent research shows that these RTK systems comodulate overlapping and dynamically adaptable oncogenic downstream signaling pathways. This study investigates how
EGFRvIII, a constitutively active EGFR deletion mutant, alters
tumor growth and signaling responses to RTK inhibition in PTEN-null/HGF(+)/c-Met(+)
glioma xenografts. We show that a neutralizing anti-HGF
monoclonal antibody (L2G7) potently inhibits
tumor growth and the activation of Akt and
mitogen-activated protein kinase (MAPK) in PTEN-null/HGF(+)/c-Met(+)/
EGFRvIII(-) U87
glioma xenografts (U87wt). Isogenic
EGFRvIII(+) U87 xenografts (U87-EGFRvIII), which grew five times more rapidly than U87-wt xenografts, were unresponsive to
EGFRvIII inhibition by
erlotinib and were only minimally responsive to anti-HGF
monoclonal antibodies.
EGFRvIII expression diminished the magnitude of Akt inhibition and completely prevented MAPK inhibition by L2G7. Despite the lack of response to L2G7 or
erlotinib as single agents, their combination synergized to produce substantial antitumor effects (inhibited
tumor cell proliferation, enhanced apoptosis, arrested
tumor growth, prolonged animal survival), against subcutaneous and orthotopic U87-EGFRvIII xenografts. The dramatic response to combining HGF:c-Met and
EGFRvIII pathway inhibitors in U87-EGFRvIII xenografts occurred in the absence of Akt and MAPK inhibition. These findings show that combining c-Met and
EGFRvIII pathway inhibitors can generate potent antitumor effects in PTEN-null
tumors. They also provide insights into how
EGFRvIII and c-Met may alter signaling networks and reveal the potential limitations of certain biochemical
biomarkers to predict the efficacy of RTK inhibition in genetically diverse
cancers.