Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies <i>TOP2A</i> as a Therapeutic Target for Rectal Cancer
Rectal cancer is a common disease with high mortality rates and limited therapeutic options. Here we combined the gene expression signatures of rectal cancer patients with the reverse drug-induced gene-expression profiles to identify drug repositioning candidates for cancer therapy. Among the predic...
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| Autores principales: | , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/2f8dc78127b245109a3a9f766d7f5edc |
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| Sumario: | Rectal cancer is a common disease with high mortality rates and limited therapeutic options. Here we combined the gene expression signatures of rectal cancer patients with the reverse drug-induced gene-expression profiles to identify drug repositioning candidates for cancer therapy. Among the predicted repurposable drugs, topoisomerase II inhibitors (doxorubicin, teniposide, idarubicin, mitoxantrone, and epirubicin) presented a high potential to reverse rectal cancer gene expression signatures. We showed that these drugs effectively reduced the growth of colorectal cancer cell lines closely representing rectal cancer signatures. We also found a clear correlation between topoisomerase 2A (<i>TOP2A)</i> gene copy number or expression levels with the sensitivity to topoisomerase II inhibitors. Furthermore, CRISPR-Cas9 and shRNA screenings confirmed that loss-of-function of the <i>TOP2A</i> has the highest efficacy in reducing cellular proliferation. Finally, we observed significant <i>TOP2A</i> copy number gains and increased expression in independent cohorts of rectal cancer patients. These findings can be translated into clinical practice to evaluate <i>TOP2A</i> status for targeted and personalized therapies based on topoisomerase II inhibitors in rectal cancer patients. |
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