MDP, a database linking drug response data to genomic information, identifies dasatinib and statins as a combinatorial strategy to inhibit YAP/TAZ in cancer cells.

Abstract

Targeted anticancer therapies represent the most effective pharmacological strategies in terms of clinical responses. In this context, genetic alteration of several oncogenes represents an optimal predictor of response to targeted therapy. Integration of large-scale molecular and pharmacological data from cancer cell lines promises to be effective in the discovery of new genetic markers of drug sensitivity and of clinically relevant anticancer compounds. To define novel pharmacogenomic dependencies in cancer, we created the Mutations and Drugs Portal (MDP, http://mdp.unimore.it), a web accessible database that combines the cell-based NCI60 screening of more than 50,000 compounds with genomic data extracted from the Cancer Cell Line Encyclopedia and the NCI60 DTP projects. MDP can be queried for drugs active in cancer cell lines carrying mutations in specific cancer genes or for genetic markers associated to sensitivity or resistance to a given compound. As proof of performance, we interrogated MDP to identify both known and novel pharmacogenomics associations and unveiled an unpredicted combination of two FDA-approved compounds, namely statins and Dasatinib, as an effective strategy to potently inhibit YAP/TAZ in cancer cells.

• Authors: Cristian Taccioli, Giovanni Sorrentino, Alessandro Zannini, Jimmy Caroli, Domenico Beneventano, Laura Anderlucci, Marco Lolli, Silvio Bicciato, Giannino Del Sal
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 36 Pg. 38854-65 (Nov 17 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26513174 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Phosphoproteins
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• Acyltransferases
• TAFAZZIN protein, human
• Dasatinib

Topics

• Acyltransferases
• Adaptor Proteins, Signal Transducing (antagonists & inhibitors, genetics, metabolism)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Dasatinib (pharmacology)
• Databases, Genetic
• Databases, Pharmaceutical
• HT29 Cells
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Pharmacogenetics (methods)
• Phosphoproteins (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• YAP-Signaling Proteins