Relevance of transcription to topoisomerase II-mediated cancer treatments
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Abstract
Cancer treatments with classic cytotoxic drugs are constrained by the resistance of cancer cells and indiscriminate toxicity towards normal cells. They are gradually being replaced by the drugs and molecules targeting cancer-specific molecules and processes. However, only a few of such targeted drugs provide clinical benefits compared to cost-effective classical drugs. Herein, I investigated an unexplored approach of improving the efficacy of the classical anti-cancer drug etoposide. I hypothesized that the response to etoposide, a widely used topoisomerase II poison, can be safely enhanced by considering treatment-evoked gene expression changes. To this end, I analyzed the basal transcriptomes and etoposide-evoked transcriptional changes in fibrosarcoma and acute myeloid leukemia (AML) cell lines. Using two parallel approaches of co-regulation within gene expression networks and essentiality for cancer cell survival, I identified and validated druggable drivers of etoposide cytotoxicity. Drivers with pre-treatment expression modulating the etoposide cytotoxicity (e.g. BIRC5 and PARP9) synergized with etoposide. Drivers essential for cancer cell survival and repressed after etoposide treatment (e.g. PFKP and PLK1) contributed to its cytotoxicity by evoking cell death. Drivers with etoposide-like gene expression changes (e.g. ANLN and MYC) synergized with etoposide as well as exhibited standalone cytotoxicity. Altogether, both pre-treatment gene expression levels and treatment-evoked gene expression changes drive the etoposide cytotoxicity. These drivers could be targeted to potentially replace etoposide or to enhance its efficacy. This approach can further be used to identify replacements and rational combination partners of other classical anti-cancer drugs interfering with gene expression.