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Simple Summary  Rectal 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.    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.

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