Drug repositioning based on the reversal of gene expression signatures identifies top2a as a therapeutic target for rectal cancer

Robson Francisco Carvalho*, Luisa Matos Do Canto, Sarah Santiloni Cury, Torben Frøstrup Hansen, Lars Henrik Jensen, Silvia Regina Rogatto

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Abstrakt

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.

OriginalsprogEngelsk
Artikelnummer5492
TidsskriftCancers
Vol/bind13
Udgave nummer21
Antal sider22
ISSN2072-6694
DOI
StatusUdgivet - 30. okt. 2021

Bibliografisk note

Funding Information:
Acknowledgments: The results shown here are in part based upon data generated by the Genotype-Tissue Expression project (GTEx) (https://gtexportal.org/) and by the TCGA Research Network (http://cancergenome.nih.gov/). The GTEX data were obtained from OCTAD (http://octad.org/) on 23 March 2021. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. OCTAD also uses compound-induced gene expression profiles from cancer cell lines using data downloaded from the LINCS [28,33,34] Consortium, an NIH Common Fund program. The authors would also like to thank researchers at the Broad Institute who released or made data available to the public through The Cancer Dependency Map (DepMap; https:// depmap.org/). DepMap is partially funded by Cancer Target Discovery and Development (CTD2), the Achilles consortium, and The Carlos Slim Foundation in Mexico through the Slim Initiative for Genomic Medicine.

Funding Information:
This research was funded by the Region of Southern Denmark Research Fund (Efond. 519, J.nr. 20/14277 to SRR), Denmark, The Danish Colorectal Cancer Center (to SRR, TFN, and LHJ), Denmark, the Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior?Brasil (CAPES)? Finance Code 001 (CAPES-PrInt-UNESP project; to RFC) and Santander Universidades (Banco Santander, Brasil, S/A; to RFC). The results shown here are in part based upon data generated by the Genotype-Tissue Expression project (GTEx) (https://gtexportal.org/) and by the TCGA Research Network (http://cancergenome.nih.gov/). The GTEX data were obtained from OCTAD (http://octad.org/) on 23 March 2021. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. OCTAD also uses compound-induced gene expression profiles from cancer cell lines using data downloaded from the LINCS [28,33,34] Consortium, an NIH Common Fund program. The authors would also like to thank researchers at the Broad Institute who released or made data available to the public through The Cancer Dependency Map (DepMap; https:// depmap.org/). DepMap is partially funded by Cancer Target Discovery and Development (CTD2), the Achilles consortium, and The Carlos Slim Foundation in Mexico through the Slim Initiative for Genomic Medicine.

Funding Information:
Funding: This research was funded by the Region of Southern Denmark Research Fund (Efond. 519, J.nr. 20/14277 to SRR), Denmark, The Danish Colorectal Cancer Center (to SRR, TFN, and LHJ), Denmark, the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)— Finance Code 001 (CAPES-PrInt-UNESP project; to RFC) and Santander Universidades (Banco Santander, Brasil, S/A; to RFC).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

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