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

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

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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

Correspondence to:

Christophe Erneux, email: [email protected]

Jean-Marie Vanderwinden, email: [email protected]

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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