Predicting chemotherapeutic drug combinations through gene network profiling

Abstract

Contemporary chemotherapeutic treatments incorporate the use of several agents in combination. However, selecting the most appropriate drugs for such therapy is not necessarily an easy or straightforward task. Here, we describe a targeted approach that can facilitate the reliable selection of chemotherapeutic drug combinations through the interrogation of drug-resistance gene networks. Our method employed single-cell eukaryote fission yeast (Schizosaccharomyces pombe) as a model of proliferating cells to delineate a drug resistance gene network using a synthetic lethality workflow. Using the results of a previous unbiased screen, we assessed the genetic overlap of doxorubicin with six other drugs harboring varied mechanisms of action. Using this fission yeast model, drug-specific ontological sub-classifications were identified through the computation of relative hypersensitivities. We found that human gastric adenocarcinoma cells can be sensitized to doxorubicin by concomitant treatment with cisplatin, an intra-DNA strand crosslinking agent, and suberoylanilide hydroxamic acid, a histone deacetylase inhibitor. Our findings point to the utility of fission yeast as a model and the differential targeting of a conserved gene interaction network when screening for successful chemotherapeutic drug combinations for human cells.

Crystal structure and functional analysis of human C1ORF123

“…S7A ) and topoisomerase II inhibitor doxorubicin (DOXO) ( Fig. S7B ), which disrupts S-phase progression, and obstructs cell cycle events including chromosome segregation, respectively ( Tay et al, 2013 ; Nguyen et al, 2015 ; Nguyen et al, 2016 ). All these observations suggest that SpEss1 is not directly involved in cell cycle control.…”

“…PCR with locus specific primers were performed to confirm the gene deletion. Previously published procedures to culture and test drug hypersensitivity in fission yeast were followed ( Tay et al, 2013 ; Nguyen et al, 2016 ). Briefly, cells were grown in YEA (3% glucose, 0.5% yeast extract, 75 mg/ml L-adenine) to log-phase, ten-fold serial-diluted and spotted onto media agar plates incorporated with drugs: hydrogen peroxide (H 2 O 2 ), hydroxyurea (HU) (Sigma-Aldrich) and doxorubicin (Wako Pure Chemical Industries Ltd, Japan).…”

“… Δ cds 1 and Δ rav 1 are null mutants of the Cds1 replication checkpoint effector kinase and assembly factor of vacuolar-ATPase, which were employed as positive controls to show hypersensitivity to HU and DOXO respectively as in previous work ( Nguyen et al, 2016 ). …”

PomBase: The Scientific Resource for Fission Yeast

“…In addition, fission yeast is used extensively as a complementary organism by those studying conserved cellular mechanisms in vertebrate systems, including the cell cycle, cytokinesis, chromosome segregation, epigenetic mechanisms, DNA metabolism, and drug responses [7][8][9][10]. PomBase thus serves a large (~15,000 unique users per month) and varied user base with diverse experience and requirements.…”

Drug combinatorics and side effect estimation on the signed human drug-target network

“…Machine learning techniques aimed at extending the target space of already approved drugs are reviewed in [ 21 ], while in [ 22 ] it is shown how to use constraint based computational methods for metabolic drug repurposing. Another line of research deals with predicting drug combinatorics via gene profiling and gene network reconstruction [ 23 ]. As surveyed in [ 10 ], the number of datasets and tools specifically dedicated to the analysis of drug-target networks has grown rapidly in the last years.…”