A Computational Drug Repositioning Approach for Targeting Oncogenic Transcription Factors.

TitleA Computational Drug Repositioning Approach for Targeting Oncogenic Transcription Factors.
Publication TypeJournal Article
Year of Publication2016
AuthorsGayvert KM, Dardenne E, Cheung C, Boland MRegina, Lorberbaum T, Wanjala J, Chen Y, Rubin MA, Tatonetti NP, Rickman DS, Elemento O
JournalCell Rep
Date Published2016 Jun 14

Mutations in transcription factor (TF) genes are frequently observed in tumors, often leading to aberrant transcriptional activity. Unfortunately, TFs are often considered undruggable due to the absence of targetable enzymatic activity. To address this problem, we developed CRAFTT, a computational drug-repositioning approach for targeting TF activity. CRAFTT combines ChIP-seq with drug-induced expression profiling to identify small molecules that can specifically perturb TF activity. Application to ENCODE ChIP-seq datasets revealed known drug-TF interactions, and a global drug-protein network analysis supported these predictions. Application of CRAFTT to ERG, a pro-invasive, frequently overexpressed oncogenic TF, predicted that dexamethasone would inhibit ERG activity. Dexamethasone significantly decreased cell invasion and migration in an ERG-dependent manner. Furthermore, analysis of electronic medical record data indicates a protective role for dexamethasone against prostate cancer. Altogether, our method provides a broadly applicable strategy for identifying drugs that specifically modulate TF activity.

Alternate JournalCell Rep
PubMed ID27264179
PubMed Central IDPMC4912004
Grant ListR01 CA194547 / CA / NCI NIH HHS / United States