Abstract
A122
17-AAG, the first-generation clinical Hsp90 inhibitor, exhibited promising anti-tumor activity in early stage clinical studies, but is limited by poor solubility and hepatotoxicity. To pursue compounds with better biopharmaceutical properties, we have developed a series of fully synthetic orally bioavailable inhibitors of Hsp90. Here we report that 17-AAG and other ansamycin drugs are inactive in P-gp and/or MRP-1 expressing cell lines and sensitivity could be restored by co-administration of P-gp or MRP inhibitors. In contrast, the synthetic Hsp90 inhibitors were active in these models. The synthetic Hsp90 inhibitors that were affected by P-gp were only modestly so, and MRP was not a factor. Accordingly, synthetic Hsp90 inhibitors were considerably more active than 17-AAG against adrenocortical carcinoma, a tumor that naturally expresses P-gp, both in vitro and in vivo. Interestingly, although 17-AAG was shown to be a good substrate for P-gp, unlike many other P-gp substrates, it exhibited no inhibitory activity against P-gp. Efflux pump-mediated resistance is manifested in both cytotoxicity assays and measurements of target inhibition, such as client protein degradation and biomarker secretion. By contrast, other resistance pathways, which also block 17-AAG activity, are operated exclusively downstream of client effects. For instance, the cytotoxic activity of the synthetic molecules was not influenced by Rb deletion or Bcl-2 over-expression, molecular lesions that don’t prevent client loss but are nonetheless associated with reduced cell killing by 17-AAG. Our results indicate that the activity of 17-AAG and other ansamycins may be curtailed in tumors that have upregulated efflux pumps or antiapoptotic proteins or dysregulated Rb signaling. These data indicate that the new generation of synthetic anti-Hsp90 drugs, exemplified by BIIB021 that is currently completing Phase I testing, may have broader application against tumors with acquired multidrug resistance or tumors located in organs protected by MDR proteins, such as the adrenal glands, brain and testis. Cancers possessing common lesions in survival signaling pathways associated with poor clinical outcome could also benefit from this treatment.
AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics-- Oct 22-26, 2007; San Francisco, CA