Phosphodiesterase 3A: a new player in development of interstitial cells of Cajal and a prospective target in gastrointestinal stromal tumors (GIST).

Pierre Vandenberghe,Perrine Hagué,Christophe Erneux,Vincent C Manganiello,Steven C Hockman,Jean-Marie Vanderwinden,Pieter Demetter

doi:10.18632/oncotarget.17010

Abstract

We previously identified phosphodiesterase 3A (PDE3A) as a marker for interstitial cells of Cajal (ICC) in adult mouse gut. However, PDE3A expression and function during gut development and in ICC-derived gastrointestinal stromal tumors (GIST) remained unknown. Here we found that PDE3A was expressed throughout ICC development and that ICC density was halved in PDE3A-deficient mice. In the human imatinib-sensitive GIST882 cell line, the PDE3 inhibitor cilostazol halved cell viability (IC50 0.35 μM) and this effect synergized with imatinib (Chou-Talalay's CI50 0.15). Recently the compound 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP was found to be cytotoxic selectively for cells expressing both PDE3A and Schlafen12 (SLFN12) (de Waal L et al. Nat Chem Bio 2016), identifying a new, non-catalytic, role for PDE3A. 108 out of 117 (92%) of our human GIST samples displayed both PDE3A and SLFN12 immunoreactivity. GIST882 cells express both PDE3A and SLFN12 and DNMDP decreased their viability by 90%. Our results suggest a role for PDE3A during ICC development and open novel perspectives for PDE3A in targeted GIST therapy, on one hand by the synergism between imatinib and cilostazol, a PDE3 inhibitor already in clinical use for other indications, and, on the other hand, by the neomorphic, druggable, PDE3A-SLFN12 cytotoxic interplay.

Highlights

Gastrointestinal stromal tumors (GIST) are the most common sarcoma of the gastrointestinal tract
Our results suggest a role for phosphodiesterase 3A (PDE3A) during interstitial cells of Cajal (ICC) development and open novel perspectives for PDE3A in targeted gastrointestinal stromal tumors (GIST) therapy, on one hand by the synergism between imatinib and cilostazol, a PDE3 inhibitor already in clinical use for other indications, and, on the other hand, by the neomorphic, druggable, PDE3A-SLFN12 cytotoxic interplay
Double IF showed that the signals for hPDE3A Ab and mPDE3A Ab colocalized in the same interstitial cells in the muscularis propria of the mouse gut, indicating that the hPDE3A antibody was appropriate to recognize mouse PDE3A (Figure 1A)

Summary

Introduction

Gastrointestinal stromal tumors (GIST) are the most common sarcoma of the gastrointestinal tract. STI-571 (imatinib mesylate, GleevecTM), the first tyrosine kinase inhibitor targeting KIT to be used in the clinics, epitomizes the targeted therapy approach. It remains nowadays the first-line medication for GIST patients, most patients will progress under treatment [2]. Despite subsequent introduction of novel selective KIT inhibitors [3], [4], primary resistance and escapes during treatment remain major concerns in GIST therapy [5]. Studies of the signaling pathways downstream of the KIT RTK and its oncogenic mutant forms remain essential to refine GIST targeted therapy

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