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

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MetadadosDescriçãoIdioma
Autor(es): dc.contributorUniversity Hospital of Southern Denmark-
Autor(es): dc.contributorUniversity of Southern Denmark-
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.contributorDanish Colorectal Cancer Center South-
Autor(es): dc.creatorCarvalho, Robson Francisco-
Autor(es): dc.creatorCanto, Luisa Matos Do-
Autor(es): dc.creatorCury, Sarah Santiloni-
Autor(es): dc.creatorHansen, Torben Frøstrup-
Autor(es): dc.creatorJensen, Lars Henrik-
Autor(es): dc.creatorRogatto, Silvia Regina-
Data de aceite: dc.date.accessioned2025-08-21T18:00:23Z-
Data de disponibilização: dc.date.available2025-08-21T18:00:23Z-
Data de envio: dc.date.issued2022-05-01-
Data de envio: dc.date.issued2022-05-01-
Data de envio: dc.date.issued2021-10-31-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.3390/cancers13215492-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/233750-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/233750-
Descrição: dc.descriptionRectal 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.-
Descrição: dc.descriptionNational Cancer Institute-
Descrição: dc.descriptionNational Heart, Lung, and Blood Institute-
Descrição: dc.descriptionNational Institute on Drug Abuse-
Descrição: dc.descriptionNational Institute of Mental Health-
Descrição: dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)-
Descrição: dc.descriptionDepartment of Clinical Genetics University Hospital of Southern Denmark-
Descrição: dc.descriptionInstitute of Regional Health Research University of Southern Denmark-
Descrição: dc.descriptionDepartment of Functional and Structural Biology—Institute of Bioscience São Paulo State University (UNESP)-
Descrição: dc.descriptionDepartment of Oncology University Hospital of Southern Denmark-
Descrição: dc.descriptionDanish Colorectal Cancer Center South-
Descrição: dc.descriptionDepartment of Functional and Structural Biology—Institute of Bioscience São Paulo State University (UNESP)-
Descrição: dc.descriptionCAPES: 001-
Idioma: dc.languageen-
Relação: dc.relationCancers-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subjectDrug repositioning-
Palavras-chave: dc.subjectDrug reversal potency scoring-
Palavras-chave: dc.subjectGene expression features-
Palavras-chave: dc.subjectRectal cancer-
Palavras-chave: dc.subjectReverse expression of signature genes-
Título: dc.titleDrug repositioning based on the reversal of gene expression signatures identifies top2a as a therapeutic target for rectal cancer-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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