Abstract
HSP90 is a component of a molecular chaperone complex that promotes the conformational maturation and stabilization of many tumor-promoting oncoproteins, including mutant BRAF and AKT. Inhibition of HSP90 results in the destabilization and proteosomal degradation of its client proteins, resulting in potent anti-tumor activity in a broad range of cancer models. XL888 is a selective ATP-competitive inhibitor of HSP90 with a distinct binding mode relative to 17-AAG and other small molecule inhibitors. In preclinical models, XL888 has potent anti-proliferative activity against a diverse panel of 118 tumor cell lines, with a median IC50 of 8.8 nM (range 0.1-1426 nM). From this broad panel, melanoma cell lines emerge as highly sensitive to XL888. As malignant melanoma is frequently characterized by elevated MAPK pathway signaling through gain of function mutations in NRAS or BRAF, and elevated AKT pathway signaling through loss of PTEN, we investigated XL888 effects on both signaling pathways. Western blot analysis reveals that treatment of a panel of melanoma cell lines with XL888 results in marked reduction of the HSP90 client proteins CRAF, BRAF(V600E), and AKT with a corresponding decrease in the level of phospho-ERK and phospho-S6 levels (IC50 values range from 16-122 nM). In vivo, XL888 inhibits the growth of multiple xenograft tumor models in athymic nude mice, including the melanoma model A375, at well tolerated oral doses and schedules. In conclusion, in vitro and in vivo preclinical data demonstrate that XL888 simultaneously attenuates signaling from both MAPK and AKT pathways in melanoma cell lines and supports clinical investigation of XL888 for the treatment of malignant melanoma where these pathways are dysregulated. XL888 is currently in Phase I clinical evaluation in cancer patients.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4690.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO
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