A Computational Drug Repositioning Approach for Targeting Oncogenic Transcription Factors.
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.
Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10021, USA; Institute for Precision Medicine, Weill Cornell Medical College, New York, NY 10021, USA; Tri-Institutional Training Program in Computational Biology and Medicine, New York, NY 10065, USA.
Kaitlyn M
KM
Gayvert
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
Etienne
E
Dardenne
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
Cynthia
C
Cheung
Department of Biomedical Informatics, Columbia University, New York, NY 10027, USA.
Mary Regina
MR
Boland
Department of Biomedical Informatics, Columbia University, New York, NY 10027, USA; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.
Tal
T
Lorberbaum
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Jackline
J
Wanjala
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Yu
Y
Chen
Institute for Precision Medicine, Weill Cornell Medical College, New York, NY 10021, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
Mark A
MA
Rubin
Department of Biomedical Informatics, Columbia University, New York, NY 10027, USA.
Nicholas P
NP
Tatonetti
Institute for Precision Medicine, Weill Cornell Medical College, New York, NY 10021, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10021, USA. Electronic address: dsr2005@med.cornell.edu.
David S
DS
Rickman
Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10021, USA; Institute for Precision Medicine, Weill Cornell Medical College, New York, NY 10021, USA. Electronic address: ole2001@med.cornell.edu.
Olivier
O
Elemento
D001381:Azepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D003907:Dexamethasone / Q000494:pharmacology; D058492:Drug Repositioning / Q000379:methods*; D057286:Electronic Health Records; D006801:Humans; D053208:Kaplan-Meier Estimate; D009857:Oncogenes; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
C561695:(+)-JQ1 compound; D001381:Azepines; D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D054852:Small Molecule Libraries; D014157:Transcription Factors; D014230:Triazoles; D003907:Dexamethasone