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Epithelial to mesenchymal transition (EMT), invasion, and motility are essential steps in colorectal cancer (CRC) metastasis regulated by HIF‐1α and NF‐κB. Since HSP90 activates HIF‐1α and NF‐κB, we hypothesized that inhibition of HSP90 leads to inhibition of HIF‐1α and NF‐κB resulting in inhibition of EMT, invasion, and motility. Treatment of colorectal cancer cell lines HT‐29 and HCT‐116 with ganetespib at 50 nM for 24 h inhibited EMT (downregulated vimentin and upregulated E‐cadherin), matrigel invasion, and spheroid migration. Ganetespib treatment or HSP90 knockdown downregulated molecular pathways associated with EMT, invasion, and motility. The overexpression of HIF‐1α or NF‐κB resulted in increased EMT, invasion, and motility in both cell lines and these effects were inhibited by ganetespib. Similar effects were observed in animal xenografts treated with ganetespib. Taken together, our …