Pan-cancer ex vivo target evaluation of phosphodiesterase 3 A (PDE3A).

Phosphodiesterase 3 A (PDE3A) is a well-characterized enzyme that plays a crucial role in various cellular processes, including cAMP-mediated signaling, CREB-mediated induction of p21 and signaling through protein kinases A and G. PDE3A has also been suggested as an inflammation-associated stemness gene which upon interaction with protein SLFN12, leads to blocked protein translation and induction of apoptosis. PDE3A has been found to be highly expressed in several human cancer types including sarcomas, pancreatic ductal adenocarcinoma, non-small cell lung cancer and melanoma. PDE3A has thus emerged as a potential therapeutic cancer target. However, to fully understand the functional role and validate target potential of PDE3A in different human cancers, further research is needed. We report here a pan-cancer ex vivo study of PDE3A protein expression across 24 different cancer types represented by 59 different molecular subtypes correlated with ex vivo drug screening of PDE3A-SLFN12 molecular glue anagrelide in 250 patient derived functional tumor models. Results of the study identify highest PDE3A expression in melanomas and across different histological subtypes of sarcomas. Correlating with the expression profile of PDE3A, anagrelide was found to display best therapeutic potential in sarcomas with high protein expression of both PDE3A and SLFN12, though sarcoma heterogeneity warrants further subtype-specific validation.