Oncotarget

Research Papers:

Potentiation of imatinib by cilostazol in sensitive and resistant gastrointestinal stromal tumor cell lines involves YAP inhibition

Pierre Vandenberghe, Marine Delvaux, Perrine Hagué, Christophe Erneux _ and Jean-Marie Vanderwinden

PDF  |  Full Text  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2019; 10:1798-1811. https://doi.org/10.18632/oncotarget.26734

Metrics: PDF 938 views  |   Full Text 1958 views  |   ?  


Abstract

Pierre Vandenberghe1, Marine Delvaux1, Perrine Hagué1, Christophe Erneux2 and Jean-Marie Vanderwinden1

1Laboratory of Neurophysiology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium

2IRIBHM, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium

Correspondence to:

Christophe Erneux, email: cerneux@ulb.ac.be

Jean-Marie Vanderwinden, email: jmvdwin@ulb.ac.be

Keywords: KIT; PDE3A; cancer; verteporfin; drug repurposing

Received: December 10, 2018     Accepted: February 03, 2019     Published: March 05, 2019

ABSTRACT

Despite the introduction of tyrosine kinase inhibitors, gastrointestinal stromal tumors (GIST) resistance remains a major clinical challenge. We previously identified phosphodiesterase 3A (PDE3A) as a potential therapeutic target expressed in most GIST. The PDE3 inhibitor cilostazol reduced cell viability and synergized with the tyrosine kinase inhibitor imatinib (Gleevec™) in the imatinib-sensitive GIST882 cell line. Here, we found that cilostazol potentiated imatinib also in the imatinib-resistant GIST48 cell line. Cilostazol induced nuclear exclusion, hence inactivation, of the transcriptional co-activator YAP, in a cAMP-independent manner. Verteporfin, a YAP/TEAD interaction inhibitor, reduced by 90% the viability of both GIST882 and GIST48 cells. Our results highlight the potential use of compounds targeting PDE3A or YAP in combined multitherapy to tackle GIST resistance.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 26734