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.
Highlights
Gastrointestinal stromal tumors (GIST) are the most frequent sarcoma of the gastrointestinal tract and arise from interstitial cells of Cajal (ICC) or their precursors [1]
We firstly evaluated the importance of phosphodiesterase 3A (PDE3A) function in the imatinib-resistant GIST48 cell line [18] using a catalytic and a non-catalytic PDE3 inhibitor, cilostazol [19] and DNDMP [16], respectively
As the best-characterized function of PDE3 is to hydrolyze cyclic nucleotides [15], we quantified the cyclic adenosine monophosphate (cAMP) amount in GIST882 and GIST48 cells treated for 72h with 1μM imatinib, 10μM cilostazol and the combination of the two drugs (1μM imatinib +10μM cilostazol)
Summary
Gastrointestinal stromal tumors (GIST) are the most frequent sarcoma of the gastrointestinal tract and arise from interstitial cells of Cajal (ICC) or their precursors [1]. Smooth muscle cells (SMC) and ICC share common mesenchymal precursors expressing, the tyrosine kinase receptor KIT (c-kit, CD117), which remain expressed in ICC throughout life and is essential for their development and maintenance [4]. The tyrosine kinase inhibitor (TKI) imatinib mesylate (STI571, Gleevec®) epitomizes the concept of targeted therapy in GIST but, despite encouraging initial results and ongoing development of novel TKIs, resistance and relapses remain the rule [6, 7], e.g. imatinib induces a form of quiescence in many imatinib-sensitive cells, eventually resulting in acquired resistance and treatment failure [8]. New targets and original therapeutic strategies are very much needed to improve outcome and treatment tolerability [11]
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