IPI-504, a novel orally administered Hsp90 inhibitor, demonstrates anti-tumor effects in EGFR mutant, kinase inhibitor resistant NSCLC

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IPI-504 is a novel water-soluble Hsp90 inhibitor and has shown early evidence of biologic activity in patients with refractory GIST. An oral formulation of IPI-504 is now in preclinical testing in murine models of human non-small cell lung cancer (NSCLC). Hsp90 regulates the stability of proteins through its role as a protein chaperone. Many of the Hsp90 client proteins are oncoproteins and play important roles in the cell-signaling, proliferation and survival of cancer cells; these client proteins include Bcr-Abl, c-Kit, and members of the ErbB family, most notably Her 2 and epidermal growth factor receptor (EGFR). Patients with tyrosine kinase inhibitor (TKI) sensitive EGFR mutations, whose tumors initially respond to gefitinib or erlotinib, often develop resistance due to additional mutations in EGFR. To test the activity of IPI-504 in NSCLC cell lines bearing mutations in EGFR, studies were carried out in NCI-H1650 (gefitinib-sensitive, activating mutation in EGFR, del E746-A750) and NCI-H1975 (gefitinib-resistant, activating mutation in EGFR, L858R, and TKI resistance-conferring mutation in EGFR, T790M) cells. IPI-504 treatment of both cell lines in vitro resulted in degradation of EGFR and induced apoptosis, similar to previous reports using the Hsp90 inhibitor geldanamycin. These studies indicate that Hsp90 inhibition with IPI-504 can silence EGFR signaling in NSCLC cell lines bearing both activating and TKI resistance-conferring mutations. To evaluate the activity of IPI-504 in NSCLC in vivo, efficacy studies were carried out with xenografts using both cell lines. Male nu/nu athymic mice were implanted subcutaneously with 10 x 106 NCI-H1650 cells in serum free media or with 2 x 106 NCI-H1975 cells in matrigel. When the average tumor size reached 150-200 mm3, animals were randomized and assigned to treatment groups. Mice were administered vehicle or IPI-504, either orally (150 mg/kg, three times weekly) or intraperitoneally (100 mg/kg, twice weekly) for three weeks. Both treatment regimens resulted in reduced tumor burden, as shown by a significant decrease in final average tumor volume when compared to vehicle treatment groups (65-70% reduction, p<0.001). In addition to measuring effects on tumor growth, pharmacodynamic markers of Hsp90 inhibition were evaluated in a subset of tumors following IPI-504 dose administration. The levels of mutant EGFR were decreased in both models, demonstrating that the mutant protein is highly dependent upon Hsp90 for stabilization. In addition, Hsp70 levels were elevated in tumors from the IPI-504 treated mice, consistent with inhibition of Hsp90. IPI-504 is active in vivo against NSCLC cells bearing mutant EGFR, including mutations that confer resistance to TKI’s. These results provide rationale for evaluation of Hsp90 inhibition with IPI-504 in patients with EGFR mutant NSCLC, including those resistant to TKI therapy.