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

Autor:	Vandenberghe P; Laboratory of Neurophysiology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium., Delvaux M; Laboratory of Neurophysiology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium., Hagué P; Laboratory of Neurophysiology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium., Erneux C; IRIBHM, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium., Vanderwinden JM; Laboratory of Neurophysiology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2019 Mar 05; Vol. 10 (19), pp. 1798-1811. Date of Electronic Publication: 2019 Mar 05 (Print Publication: 2019).
DOI:	10.18632/oncotarget.26734
Abstrakt:	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. Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.
Databáze:	MEDLINE
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