Intratumoral heterogeneity is evident as distinct subpopulations of cancer cells within and between tumor lesions that profoundly impact therapeutic response and patient outcome. While the advent of targeted therapies to exploit a tumor's dependence on critical proliferative or survival pathways has significantly improved patient outcomes in a range of solid tumor types, it is also apparent that targeted therapeutics do not help all molecularly selected patients and even when clinical benefit is observed, it is often of limited duration. To address this question, we have explored the invariably fatal adult brain tumor glioblastoma multiforme (GBM). Heterogeneous forms of the epidermal growth factor receptor (EGFR) arise through amplification or mutation as signature pathogenetic events in this highly aggressive disease. While EGFR deregulation promotes tumor cell proliferation, drug resistance and tumor survival, functional blockade of the EGFR kinase activity alone does not achieve maximal therapeutic benefit. Since intratumoral heterogeneity represents a major impediment to the development of effective therapeutics in GBM, we sought to identify small molecules cytotoxic to glioma cells engineered to overexpress either wildtype (WT), constitutively active mutant EGFR-vIII, kinase-dead (KD) form or a basal level of EGFR-WT using a live cell-based, high-throughput screen (HTS) of ∼2,000 FDA-approved or bioactive compounds. Our screen revealed that the Hsp90 inhibitor ganetespib (STA-9090, Synta Pharmaceuticals, Lexington, MA) was highly cytotoxic (IC50 ∼20nM) to glioma cells that overexpressed each of the EGFR forms. Real-time measurements were then performed to demonstrate that ganetespib at nM concentrations reduced the proliferation of brain tumor cells expressing EGFR-WT, -vIII or KD forms, induced apoptosis and inhibited glioma migration. Ganetespib also potently reduced the proliferation of human GBM patient-derived tumor-initiating stem cells but not that of untransformed glial cells. Ganetespib effectively impaired the growth of subcutaneously implanted human brain tumor xenotransplants that expressed either EGFR-WT, -vIII or both EGFR forms placed in immunocompromised mice. In addition, ganetespib provided a survival benefit compared to untreated mice. The Hsp90 inhibitor ganetespib is a highly potent agent that impairs the growth-promoting functional kinase-dependent and independent activities of EGFR to overcome context-dependent intratumoral heterogeneity with potential benefits for GBM patients.

Citation Format: James J. Driscoll, Nitin S. Narayanan, Sajjeev Jagannathan. The Hsp90 inhibitor ganetespib overcomes EGFR-based intratumoral heterogeneity to block glioma proliferation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-140. doi:10.1158/1538-7445.AM2014-LB-140

©2014 American Association for Cancer Research.
2014