The cAMP pathway is both important for normal melanocyte biology and implicated in melanoma development. We have shown that transformation of melanocytes by oncogenic BRAF inhibits cAMP signalling. This inhibition is due to overexpression of the phosphodiesterase PDE4D, enzyme that physiologically degrades cAMP. PDE4D expression is increased in patients with advanced melanoma and promotes melanoma invasion. Our recent work shows that PDE4D is overexpressed in BRAF-mutated melanoma cells which are resistant to BRAF inhibitors. PDE4D overexpression seems to be linked to loss of methylation in CpG islands upstream of the PDE4D promoter and may induce resistance by allowing CRAF reactivation. We showed that inhibiting PDE4D by chemical inhibitor or RNA interference significantly reduced clone formation in resistant melanoma cell lines. Inhibition of PDE4D also reduced the proliferation of melanoma cells grown as spheroids. This is confirmed in a mouse xenograft model where PDE4D inhibition by a chemical inhibitor or RNA interference reduced tumour growth. PDE4D may therefore serve as a new therapeutic target for the treatment of melanoma resistant to targeted therapy and may prevent their emergence. Indeed, specific PDE4 inhibitors are available in the clinics and could be used as a complementary therapeutic approach for the treatment of melanoma.

The role of PDE4D in resistance to targeted therapy in melanoma