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.
Highlights
Despite the presence of targeted therapies and increasing number of genomic biomarkers, cytotoxic chemotherapy, which damages cells and causes rapid cell death, remains the gold standard for most treatment of most cancers [1,2,3,4]
Unlike target-specific drugs, cytotoxic drugs result in highly variable patient outcomes, making the prediction of responsiveness challenging using genomic profiles, which can otherwise provide some insights into nonspecific antiproliferative or cytotoxic effects [9]
We analyzed 407 Genomics of Drug Sensitivity in Cancer (GDSC) cancer cell lines to identify somatic mutation profiles, copy number estimations, and IC50 values for paclitaxel [19]. This led to the identification of 142 Synthetic cytotoxicity (SC) pairs of mutated genes by integrating the mutational and drug sensitivity profiles (Figure 1)
Summary
Despite the presence of targeted therapies and increasing number of genomic biomarkers, cytotoxic chemotherapy, which damages cells and causes rapid cell death, remains the gold standard for most treatment of most cancers [1,2,3,4]. Oncogene-targeting inhibitors are effective for some cancer patients, not all cancer cells express these targets As another treatment option, synthetic lethal approach targets one of the negative genetic interactions in the second site, which functionally disrupts both the genes simultaneously, leading to cancer cell death [10,11]. We focused on the chemotherapeutic agent paclitaxel, and using Genomics of Drug Sensitivity in Cancer (GDSC) cell line data, we identified SC mutational pairs that increase the anticancer effect of paclitaxel via conditional synthetic lethality. We validated these findings using The Cancer Genome Atlas (TCGA) genome profiles and clinical data. Among many identified candidate SC pairs, we tested the SC partner genes of TP53, an important tumor suppressor gene with a high frequency of somatic mutation, to validate SC and the prognostic effects in patients with bladder urothelial and uterine corpus endometrial carcinoma included in TCGA
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