Evaluation of drug-targetable genes by defining modes of abnormality in gene expression.
In the post-genomic era, many researchers have taken a systematic approach to identifying abnormal genes associated with various diseases. However, the gold standard has not been established, and most of these abnormalities are difficult to be rehabilitated in real clinical settings. In addition to identifying abnormal genes, for a practical purpose, it is necessary to investigate abnormality diversity. In this context, this study is aimed to demonstrate simply restorable genes as useful drug targets. We devised the concept of "drug targetability" to evaluate several different modes of abnormal genes by predicting events after drug treatment. As a representative example, we applied our method to breast cancer. Computationally, PTPRF, PRKAR2B, MAP4K3, and RICTOR were calculated as highly drug-targetable genes for breast cancer. After knockdown of these top-ranked genes (i.e., high drug targetability) using siRNA, our predictions were validated by cell death and migration assays. Moreover, inhibition of RICTOR or PTPRF was expected to prolong lifespan of breast cancer patients according to patient information annotated in microarray data. We anticipate that our method can be widely applied to elaborate selection of novel drug targets, and, ultimately, to improve the efficacy of disease treatment.
Department of Bio and Brain Engineering, KAIST, Daejeon, 305-701, Republic of Korea.
Junseong
J
Park
Department of Bio and Brain Engineering, KAIST, Daejeon, 305-701, Republic of Korea.
Jungsul
J
Lee
Department of Bio and Brain Engineering, KAIST, Daejeon, 305-701, Republic of Korea.|KAIST Institute for the BioCentury, KAIST, Daejeon, 305-701, Republic of Korea.
Chulhee
C
Choi
D000970:Antineoplastic Agents / Q000627:therapeutic use; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins