Transcriptomics,Genomics

Dataset Information

36

Effects of inhibition of topoisomerase I or HSP90 in primary melanoma cell lines


ABSTRACT: Using 4 primary melanoma cell lines for which autologous tumor-infiltrating T lymphocytes (TILs) were available, a screen of clinically-relevant small-molecule inhibitors (SMIs) was performed to find SMIs that could synergistically enhance tumor cell killing by autologous TILs. Among positive results were SMIs targeting topoisomerase I (TOP1) or HSP90. Of note, as implied by the fact that these SMIs had synergistic effects, there was relatively little direct cytotoxicity of the SMIs when used alone. Gene expression profiling was undertaken to identify changes induced by SMIs of TOP1 or HSP90. SN38 is the active metabolite of irinotecan, a standard-of-care clinical TOP1 inhibitor. Ganetespib is a newer generation HSP90 inhibitor, reported to exhibit greater potency in preclinical tumor models and reduced toxicity in rodents, compared to other 1st and 2nd generation HSP90 inhibitors, consistent with its favorable safety profile in patients. Overall design: Each of the 4 primary melanoma cell lines was cultured in duplicate with either SN38, ganetespib, or DMSO control.

INSTRUMENT(S): Illumina HumanHT-12 V4.0 expression beadchip

SUBMITTER: Zhiqiang Wang  

PROVIDER: GSE100317 | GEO | 2017-10-04

SECONDARY ACCESSION(S): PRJNA391305

REPOSITORIES: GEO

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Publications


T-cell-based immunotherapies are promising treatments for cancer patients. Although durable responses can be achieved in some patients, many patients fail to respond to these therapies, underscoring the need for improvement with combination therapies. From a screen of 850 bioactive compounds, we identify HSP90 inhibitors as candidates for combination with immunotherapy. We show that inhibition of HSP90 with ganetespib enhances T-cell-mediated killing of patient-derived human melanoma cells by th  ...[more]

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