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Updated: Nov 19, 2025
A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
In Silico Inference of Synthetic Cytotoxic Interactions from Paclitaxel Responses
Jeong Hoon Lee1, Kye Hwa Lee2, Ju Han Kim1
1Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul 110799, Korea.
Abstract:
To exploit negatively interacting pairs of cancer somatic mutations in chemotherapy responses or synthetic cytotoxicity (SC), we systematically determined mutational pairs that had significantly lower paclitaxel half maximal inhibitory concentration (IC50) values. We evaluated 407 cell lines with somatic mutation profiles and estimated their copy number and drug-inhibitory concentrations in Genomics of Drug Sensitivity in Cancer (GDSC) database. The SC effect of 142 mutated gene pairs on response to paclitaxel was successfully cross-validated using human cancer datasets for urogenital cancers available in The Cancer Genome Atlas (TCGA) database. We further analyzed the cumulative effect of increasing SC pair numbers on the TP53 tumor suppressor gene. Patients with TCGA bladder and urogenital cancer exhibited improved cancer survival rates as the number of disrupted SC partners (i.e., SYNE2, SON, and/or PRY) of TP53 increased. The prognostic effect of SC burden on response to paclitaxel treatment could be differentiated from response to other cytotoxic drugs. Thus, the concept of pairwise SC may aid the identification of novel therapeutic and prognostic targets.
Insights
Identifying gene pairs with synthetic cytotoxicity (SC) can predict chemotherapy response. Increased SC partners of TP53 correlate with improved survival in urogenital cancers, suggesting new therapeutic targets.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Cancer somatic mutations can influence chemotherapy response.
- Synthetic cytotoxicity (SC) describes interactions between mutations that are lethal together.
Purpose of the Study:
- To identify gene pairs exhibiting synthetic cytotoxicity (SC) with paclitaxel treatment.
- To explore the prognostic value of SC in cancer patients.
Main Methods:
- Systematic analysis of 407 cell lines' somatic mutation profiles and drug sensitivity data from the Genomics of Drug Sensitivity in Cancer (GDSC) database.
- Cross-validation of 142 identified SC gene pairs using The Cancer Genome Atlas (TCGA) urogenital cancer datasets.
- Evaluation of the cumulative effect of SC pairs on TP53 and its correlation with patient survival.
Main Results:
- Identified specific gene pairs with significantly lower paclitaxel half maximal inhibitory concentration (IC50) values, indicating SC.
- Validated the SC effect of 142 gene pairs in TCGA urogenital cancer datasets.
- Demonstrated that an increased number of disrupted SC partners of TP53 (SYNE2, SON, PRY) is associated with improved survival rates in bladder and urogenital cancer patients.
- Showed that the prognostic effect of SC burden on paclitaxel response is distinct from other cytotoxic drugs.
Conclusions:
- Pairwise synthetic cytotoxicity (SC) is a viable strategy for predicting chemotherapy response.
- SC burden, particularly involving TP53, serves as a potential prognostic biomarker for urogenital cancers.
- The concept of pairwise SC can guide the discovery of novel therapeutic and prognostic targets in oncology.
