Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies TOP2A as a Therapeutic Target for Rectal Cancer.

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

doi:10.3390/cancers13215492

Robson Francisco Carvalho, Lars Henrik Jensen + Show 4 more

Open Access

https://doi.org/10.3390/cancers13215492

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Abstract

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.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.

Highlights

Cancer is one of the leading causes of death worldwide [1]
We found that topoisomerase and cyclin-dependent kinase (CDK) inhibitors potentially reverse ReCa signatures and inhibit the growth of colorectal cancer (CRC) cell lines closely representing ReCa signatures
We explored and compared publicly available gene expression profiles of ReCa with those of multiple cancer cell lines treated with drugs in clinical trials or Food and Drug Administration (FDA)-approved to identify drugs with potency to reverse gene expression signatures of the disease

Summary

Introduction

Cancer is one of the leading causes of death worldwide [1]. the discovery and translation of new drugs for cancer treatment is costly [2], requires years of research and development [3,4], and only a few drugs entering clinical trials are eventually approved for clinical use [5,6]. The definition of drug repositioning ( called drug repositioning, reprofiling, or re-tasking) has been explored since the publication of Ashburn and Thor in 2004 [9] According to these authors, drug repositioning is the process of identifying and developing new uses for approved drugs or those under investigation outside the original indication [9]. Repositioning drugs approved by regulatory agencies or currently in clinical trials are valuable alternatives for finding new cancer therapies that can be rapidly translated to the clinic [10]. This approach can benefit cancer patients by increasing the number of new therapeutic indications to non-oncology drugs or improving the effectiveness of personalized and targeted therapies [11]

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