Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies TOP2A 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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Bibliographic Details
Published in:Cancers 2021-10, Vol.13 (21), p.5492
Main Authors: Carvalho, Robson Francisco, do Canto, Luisa Matos, Cury, Sarah Santiloni, Frøstrup Hansen, Torben, Jensen, Lars Henrik, Rogatto, Silvia Regina
Format: Article
Language:English
Subjects:
5-Fluorouracil
Cancer
Cancer therapies
Candidates
Clinical trials
Colorectal cancer
Colorectal carcinoma
Copy number
CRISPR
Cyclin-dependent kinases
Datasets
DNA topoisomerase (ATP-hydrolysing)
Doxorubicin
Drug development
Drug resistance
Drugs
Epirubicin
FDA approval
Gene expression
Kinases
Medical Subject Headings-MeSH
Mitoxantrone
Patients
Radiation therapy
Rectum
Teniposide
Therapeutic targets
Tumor cell lines
Tumors
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Summary: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 (TOP2A) 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 TOP2A has the highest efficacy in reducing cellular proliferation. Finally, we observed significant TOP2A copy number gains and increased expression in independent cohorts of rectal cancer patients. These findings can be translated into clinical practice to evaluate TOP2A status for targeted and personalized therapies based on topoisomerase II inhibitors in rectal cancer patients.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13215492