Biological effects of the novel small molecule Hsp90 inhibitor SNX-2112 as a single agent and in combination with Erlotinib in non-small cell lung cancer models

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The molecular chaperone Hsp90 plays a central role in maintaining the functional conformation of numerous important oncoproteins. Initial clinical trials with 17-AAG, an analog of the natural product geldanamycin, have shown promising results in several oncology indications and have validated Hsp90 as a target for therapeutic intervention. However, 17-AAG has several inherent chemical characteristics which minimize its effective use in a wide range of clinical applications, particularly the chemical reactivity of its core quinone and the requirement for IV dosing. Serenex has developed the novel small-molecule Hsp90 inhibitor SNX-2112. In pre-clinical testing, SNX-2112 and its prodrug SNX-5422 have shown potent effects on cancer cell proliferation, degradation of key Hsp90 client proteins, and activity as an orally delivered agent in all mouse xenograft models tested.
 In non-small cell lung cancer (NSCLC), Epidermal Growth Factor Receptor (EGFR) kinase inhibitors have shown remarkable results as initial treatment options in specific cases. However, a number of mutations in EGFR that confer resistance to these kinase inhibitors have recently been described. Hsp90 has been shown to facilitate folding of these EGFR mutants to the degree that they degrade more rapidly than wild type EGFR protein (Cancer Res. 2005;65[14], 6401-6408). These results suggested that SNX-2112 would be effective as a treatment in NSCLC.
 SNX-2112, delivered orally as SNX-5422, has exhibited potent effects as a single agent and in combination with erlotinib in both the A431 EGFR -over expressing xenograft model (ED50 ~25 mg/kg 3X weekly PO) and the NCI-H1975 mutant-EGFR xenograft model (ED50 ~15 mg/kg 3X weekly PO). Cellular experiments demonstrated that SNX-2112, as both a single agent and in combination with erlotinib, acts to reduce signaling through the AKT, ERK, and STAT3 signaling cascades in A431 and NCI-H1975 cells with potencies of 10-30 nM. In combination, effects on phospho-oncoprotein levels are prolonged and attenuated as compared to those achieved with erlotinib alone. Treatment with SNX-2112 also results in the time and dose dependent degradation of c-MET receptor in these cell lines. Cross-talk from EGF receptor activation to the c-MET receptor is suppressed in A431 cells treated with erlotinib and this effect is further prolonged and attenuated in combination with SNX-2112. These results indicate that SNX-2112, alone or in combination with an EGFR kinase inhibitor is a viable option for the treatment of NSCLC, particularly erlotinib-resistant NSCLC.