Potentiation of imatinib by cilostazol in sensitive and resistant gastrointestinal stromal tumor cell lines involves YAP inhibition
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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
Christophe Erneux, email: email@example.com
Jean-Marie Vanderwinden, email: firstname.lastname@example.org
Keywords: KIT; PDE3A; cancer; verteporfin; drug repurposing
Received: December 10, 2018 Accepted: February 03, 2019 Published: March 05, 2019
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.
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