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.

Glucocorticoid receptor signalling activates YAP in breast cancer

“…Indeed, in cells grown on high-rigidity substrate under high mechanical tensions generated by actin stress fibres YAP localizes in the nucleus and activates its transcriptional program1827. In this context, tension imposed by integrin-mediated cell adhesion to fibronectin leads to FAK/Src-mediated cytoskeleton rearrangement, cell spreading and LATS1/2-dependent YAP nuclear localization273031. Moreover, actin cytoskeleton and Src functions are required for the YAP activation by stiff matrices32.…”

Atheroprotective laminar flow inhibits Hippo pathway effector YAP in endothelial cells

“…Potential YAP inhibitors may block either YAP cytoplasmic-nuclear shuttling, YAP proteasomal degradation, or YAP-TEAD interaction 48 . Till now, several agents have been repurposed as YAP inhibitors, including verteporfin 49 , lipid-lowering statins 50–52 , and tankyrase inhibitors 53 . Verteporfin has been shown to be a potent YAP inhibitor, which suppresses YAP–TEAD interaction and transcriptional activity 49 .…”

The 2016 John J. Abel Award Lecture: Targeting the Mechanical Microenvironment in Cancer

“…However, Src inhibition through Dasatinib has been shown to oppose YAP/TAZ transcriptional effects in vitro and in vivo (Rosenbluh et al, 2012;Calvo et al, 2013). When Dasatinib is given in combination with statin treatment to inhibit Rho, it appears to have a much more significant effect on the downstream YAP/TAZ activity (Taccioli et al, 2015). This indicates that perhaps when attempting to target downstream effectors of mechanosensing pathways, it could be beneficial to hit multiple effectors at once.…”

“…Low toxicity in phase 1 trials, some disease stabilization YAP/TAZ inhibition and cytoplasmic relocalization; reduction in cancer stem cell growth and tumor xenograft models Sorrentino et al, 2014;Wang et al, 2014;Li et al, 2015 Verteporfin YAP/TAZ inhibitor Inhibits YAP-TEAD binding and suppresses downstream signaling in retinoblastoma Liu-Chittenden et al, 2012;Brodowska et al, 2014;Wang et al, 2015 Dasatinib Src inhibitor Monotherapy phase 2 trials show some effect in breast and prostate cancer and melanoma, and no benefit in other cancer types such as small cell lung cancer; combination in with statin treatment has a greater effect on downstream YAP/TAZ activity Mayer and Krop, 2010;Miller et al, 2010;Rosenbluh et al, 2012;Calvo et al, 2013;Taccioli et al, 2015 HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; GIST, gatrointestinal stromal tumor.…”