TM-03 * THE HSP90 INHIBITOR GANETESPIB IS AN EFFECTIVE THERAPY FOR GLIOBLASTOMA THAT BLOCKS EGFR-DRIVEN TUMOR GROWTH

Abstract

Malignant gliomas are highly aggressive primary brain tumors with few treatment options and invariably fatal outcomes. The receptor tyrosine kinase epidermal growth factor receptor (EGFR) is hyperactivated through gene amplification or mutation in many cancers. EGFR activity is associated with increased cell proliferation, disease progression and therapeutic resistance. Intratumoral heterogeneity of EGFR arises as a signature pathogenetic events in the highly aggressive and invariably fatal brain tumor glioblastoma multiforme (GBM). Functional blockade of the EGFR kinase activity alone does not achieve maximal therapeutic benefit to support the role for EGFR kinase-independent functions. We performed a high-throughput, pharmacologic screening to identify EGFR-targeted therapeutics in glioma cells engineered to overexpress either a high or low copy number of EGFR wildtype (WT), a constitutively active mutant EGFR-vIII or an EGFR kinase-dead (KD) mutant. We discovered that the heat shock protein (HSP)90 inhibitor ganetespib selectively and potently killed glioma cells that overexpressed either the WT, vIII or KD forms of EGFR (IC50 ∼20-40nM). Real-time measurements demonstrated that ganetespib reduced proliferation, induced caspase-dependent apoptosis and inhibited glioma migration. Overexpression of the EGFR-WT, vIII or KD forms significantly increased intracellular ATP levels and WT, vIII and KI EGFR all translocalized to the mitochondria. Ganetespib addition rapidly reduced ATP in cells that overexpressed either kinase-active or kinase-inactive forms. Ganetespib reduced the proliferation of human patient GBM patient-derived tumor stem cells and effectively impaired the growth of subcutaneously placed glioma implants in nude mouse models. Ganetespib impairs the EGFR kinase-(in)dependent activities with the potential benefit to overcome intratumoral heterogeneity benefit and improve GBM patient outcome.