<p>HSP90 Inhibitor Ganetespib (STA-9090) Inhibits Tumor Growth in c-Myc-Dependent Esophageal Squamous Cell Carcinoma</p>

Abstract

Purpose: Currently, the paucity of classical effective pharmacological drugs to treat esophageal squamous cell carcinoma (ESCC) is a major problem. The c-Myc (MYC) protein is a promising target as it is overexpressed in ESCC. MYC is a sensitive client protein of the heat shock protein 90 (HSP90) and, therefore, targeting the HSP90-MYC axis by inhibition of HSP90 is a potential therapeutic strategy for ESCC. Here, we evaluated the clinical application value of the HSP90 inhibitor (Ganetespib, STA-9090) as an anti-cancer agent for MYC-positive ESCC. Materials and Methods: We first analyzed ESCC tissue microarrays and clinical tissue samples to determine MYC expression. The relationship between MYC and HSP90 was analyzed by co-immunoprecipitation assays and immunofluorescence. In in vitro cell models, cell growth was analyzed using the CCK-8 kit, and MYC protein expression was analyzed by Western blot. The in vivo antitumor activity of STA-9090 was assessed in two xenograft animal models. Results: We demonstrated that MYC-overexpressing ESCC cells were highly sensitive to STA-9090 treatment through suppressing ESCC cell proliferation, cell cycle progression and survival. Moreover, STA-9090 treatment decreased MYC expression, reducing the half-life of the MYC protein. We further established two xenograft mouse models using ESCC cells and clinical ESCC samples to validate the effectiveness of STA-9090 in vivo. In both xenograft models, STA-9090 substantially inhibited the growth of MYC-positive ESCC tumors in vivo. In contrast, STA-9090 treatment demonstrated no beneficial effects in mice with low-MYC expressing ESCC tumors. Conclusion: In conclusion, our data support that the HSP90 inhibitor, STA-9090, suppresses the expression of the MYC protein and interferes with HSP90-MYC protein-protein interaction. This, in turn, leads to inhibition of ESCC cell proliferation and promotion of apoptosis in ESCC cells in vitro and reduction of ESCC tumors in vivo. We propose, based on our findings, that STA-9090 is a potential novel therapeutic target for MYC-positive ESCC.

HSP90 inhibition downregulates DNA replication and repair genes via E2F1 repression

“…Guan et al . ( 45 ) found that ganetespib treatment caused an increase in cell cycle–dependent kinase inhibitors p15 and p21 in c-Myc–dependent esophageal squamous cell carcinoma. Ganetespib significantly represses CDK1 expression and caused G2 block and mitotic arrest in thyroid cancer cells ( 46 ).…”

Harnessing the Heterogeneity of Prostate Cancer for Target Discovery Using Patient-Derived Explants

“…E2F1 has been attributed to numerous cancer hallmarks in prostate cancer, including cell cycle, proliferation and apoptosis [ 45 ], and its expression is so closely aligned with disease stage that it has been proposed as a potential biomarker [ 46 , 47 ]. Notably, AR, MYC and E2F1/2 are all established Hsp90 client proteins, and targeting Hsp90 inhibits expression of AR in prostate cancer (reviewed in [ 41 ]), and MYC [ 48 , 49 , 50 , 51 ] and E2F1 [ 52 , 53 ] in other cancers. Our ability to identify known pathways associated with Hsp90 and prostate cancer through omics analysis of PDE tissues highlights the capacity for omics identification of novel targets and biomarkers in the face of prostate tumor heterogeneity.…”

Patient-derived xenograft: a developing tool for screening biomarkers and potential therapeutic targets for human esophageal cancers

“…cisplatin) and radiation play inhibitory roles in EC cell survival. For instance, the inhibitor of HSP90 Ganetespib (STA-9090) could inhibit cell proliferation and induce apoptosis in ESCC cells and PDX models [ 148 ]. Interestingly, the effect of HSP90 inhibition seemed to be dependent on MYC expression.…”

“…Interestingly, the effect of HSP90 inhibition seemed to be dependent on MYC expression. ESCC cells and xenografted primary tumors overexpressing MYC were more sensitive to STA-9090 [ 148 ].…”