BioProject

Recently approved cancer drugs remain out-of-reach to most patients due to prohibitive costs and only few produce clinically meaningful benefits. More...

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 treatments. We hypothesized that the response to topoisomerase II poisons, the most successful group of cancer drugs, can be improved by considering treatment-associated transcript levels, taken as surrogates for protein expression. 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 the drug. 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. Inhibitors of protein products of the involved genes can be used 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. Overall design: AML cell lines were treated with either vehicle control (media) or cell-specific IC50 concentrations of etoposide for 24 hours. Total RNA was extracted and single-end RNA sequencing was performed to idendify etoposide-evoked changes in the gene expression. The experiment was perfomed using 3 biological replicates, each for vehicle control- and etoposide-treated cells. Less...