Research Papers:

Drivers of topoisomerase II poisoning mimic and complement cytotoxicity in AML cells

Piyush More, Ute Goedtel-Armbrust, Viral Shah, Marianne Mathaes, Thomas Kindler, Miguel A. Andrade-Navarro and Leszek Wojnowski _

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Oncotarget. 2019; 10:5298-5312. https://doi.org/10.18632/oncotarget.27112

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Piyush More1, Ute Goedtel-Armbrust1, Viral Shah2,3, Marianne Mathaes1, Thomas Kindler2,3, Miguel A. Andrade-Navarro4 and Leszek Wojnowski1

1 Department of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany

2 Department of Hematology, Medical Oncology and Pneumology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany

3 University Cancer Center of Mainz, Mainz, Germany

4 Computational Biology and Data Mining, Faculty of Biology, Johannes Gutenberg University Mainz, Mainz, Germany

Correspondence to:

Leszek Wojnowski,email: [email protected]

Keywords: topoisomerase II poisons; DNA damage; gene expression; combination therapy; cancer essentiality

Received: April 24, 2019     Accepted: June 19, 2019     Published: September 03, 2019


Recently approved cancer drugs remain out-of-reach to most patients due to prohibitive costs and only few produce clinically meaningful benefits. An untapped alternative is to enhance the efficacy and safety of existing cancer drugs. We hypothesized that the response to topoisomerase II poisons, a very successful group of cancer drugs, can be improved by considering treatment-associated transcript levels. To this end, we analyzed transcriptomes from Acute Myeloid Leukemia (AML) cell lines treated with the topoisomerase II poison etoposide. Using complementary criteria of co-regulation within networks and of essentiality for cell survival, we identified and functionally confirmed 11 druggable drivers of etoposide cytotoxicity. Drivers with pre-treatment expression predicting etoposide response (e.g., PARP9) generally synergized with etoposide. Drivers repressed by etoposide (e.g., PLK1) displayed standalone cytotoxicity. Drivers, whose modulation evoked etoposide-like gene expression changes (e.g., mTOR), were cytotoxic both alone and in combination with etoposide. In summary, both pre-treatment gene expression and treatment-driven changes contribute to the cell killing effect of etoposide. Such targets can be tweaked to enhance the efficacy of etoposide. This strategy can be used to identify combination partners or even replacements for other classical anticancer drugs, especially those interfering with DNA integrity and transcription.

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