In Silico Inference of Synthetic Cytotoxic Interactions from Paclitaxel Responses.
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.
['Lee|Jeong Hoon|JH|0000-0002-1789-8270', 'Lee|Kye Hwa|KH|', 'Kim|Ju Han|JH|']
D000970:Antineoplastic Agents D002277:Carcinoma D045744:Cell Line, Tumor D003198:Computer Simulation D016889:Endometrial Neoplasms D005260:Female D053263:Gene Regulatory Networks D016147:Genes, Tumor Suppressor D015894:Genome, Human D006801:Humans D020128:Inhibitory Concentration 50 D053208:Kaplan-Meier Estimate D009154:Mutation D017239:Paclitaxel D011379:Prognosis D016016:Proportional Hazards Models D016159:Tumor Suppressor Protein p53 D001749:Urinary Bladder Neoplasms D014565:Urogenital Neoplasms
synthetic cytotoxicity paclitaxel chemotherapy response urogenital cancer conditional synthetic lethality