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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Published inCancers Vol. 13; no. 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 Journal Article
LanguageEnglish
Published Basel MDPI AG 31.10.2021
MDPI
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
Online AccessGet full text
ISSN2072-6694
2072-6694
DOI10.3390/cancers13215492

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Abstract 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.
AbstractList 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.
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.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.
Simple SummaryRectal cancer is the 8th most common cancer globally. Most patients with locally advanced rectal cancer receive neoadjuvant therapy based on 5-fluorouracil and radiotherapy showing variable responses. About 70–90% of patients present partial response, while 20% show treatment resistance. Repositioning drugs approved by regulatory agencies or drugs currently in clinical trials is a strategy to accelerate the development of drug-based cancer therapies. We compared rectal cancer gene expression signatures with reverse drug-induced gene-expression profiles of cancer cell lines to identify potential drugs for repositioning. Our analyses revealed that approved topoisomerase II inhibitors are candidate drugs for rectal cancer treatment. We also verified TOP2A copy number gains and increased expression in rectal tumors. These TOP2A alterations were independent predictive markers of topoisomerase inhibitor efficacy in colorectal cancer cells that closely represent rectal cancer signatures. Topoisomerase inhibitors are potentially helpful to treat rectal cancer patients with TOP2A imbalances.AbstractRectal 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.
Author do Canto, Luisa Matos
Cury, Sarah Santiloni
Frøstrup Hansen, Torben
Jensen, Lars Henrik
Carvalho, Robson Francisco
Rogatto, Silvia Regina
AuthorAffiliation 4 Department of Oncology, University Hospital of Southern Denmark, 7100 Vejle, Denmark; Torben.Hansen@rsyd.dk (T.F.H.); Lars.Henrik.Jensen@rsyd.dk (L.H.J.)
3 Department of Functional and Structural Biology—Institute of Bioscience, São Paulo State University (UNESP), Botucatu 18618-689, Brazil; santiloni.cury@unesp.br
5 Danish Colorectal Cancer Center South, 7100 Vejle, Denmark
2 Institute of Regional Health Research, University of Southern Denmark, 5230 Odense, Denmark
1 Department of Clinical Genetics, University Hospital of Southern Denmark, 7100 Vejle, Denmark; luisa.matos.do.canto.alvim@rsyd.dk
AuthorAffiliation_xml – name: 4 Department of Oncology, University Hospital of Southern Denmark, 7100 Vejle, Denmark; Torben.Hansen@rsyd.dk (T.F.H.); Lars.Henrik.Jensen@rsyd.dk (L.H.J.)
– name: 3 Department of Functional and Structural Biology—Institute of Bioscience, São Paulo State University (UNESP), Botucatu 18618-689, Brazil; santiloni.cury@unesp.br
– name: 1 Department of Clinical Genetics, University Hospital of Southern Denmark, 7100 Vejle, Denmark; luisa.matos.do.canto.alvim@rsyd.dk
– name: 2 Institute of Regional Health Research, University of Southern Denmark, 5230 Odense, Denmark
– name: 5 Danish Colorectal Cancer Center South, 7100 Vejle, Denmark
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Snippet Rectal cancer is a common disease with high mortality rates and limited therapeutic options. Here we combined the gene expression signatures of rectal cancer...
Simple SummaryRectal cancer is the 8th most common cancer globally. Most patients with locally advanced rectal cancer receive neoadjuvant therapy based on...
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StartPage 5492
SubjectTerms 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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Title Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies TOP2A as a Therapeutic Target for Rectal Cancer
URI https://www.proquest.com/docview/2596009088
https://www.proquest.com/docview/2597496071
https://pubmed.ncbi.nlm.nih.gov/PMC8583090
Volume 13
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