磷酸酯酶 (PDE) 是环核苷酸信号传导的关键调节因子，控制癌症的许多特征，并在非小细胞肺癌 (NSCLC) 的化疗耐药中发挥作用。我们评估了抗叶酸剂培美曲塞 (PMX) 单独或与 PDE5、8、9 或 10 生化抑制剂联合使用对鳞状和非鳞状 NCSLC 细胞的抗肿瘤活性。 PDE 基因的基因组改变 (PDEmut) 或 PDE 生化抑制 (PDEi) 可以使 NSCLC 在体外对 PMX 敏感（在评估的 50% NSCLC 中观察到）。 PDEi 与 PMX 的协同活性需要微剂量的抗叶酸药物。作为单一药物，所评估的 PDE 均不具有抗肿瘤活性。 PDE 生化抑制剂针对 cAMP 或 cGMP 信号传导（或两者），导致下游途径的显着交叉调节。 PDEi 的使用可能提出了一种克服 PDEwt NSCLC 肿瘤 PMX 耐药性的新策略，但也有重要的警告，包括使用亚治疗 PMX 剂量。

Phosphosidesterases (PDEs) are key regulators of cyclic nucleotide signaling, controlling many hallmarks of cancer and playing a role in resistance to chemotherapy in non-small-cell lung cancer (NSCLC). We evaluated the anti-tumor activity of the anti-folate agent pemetrexed (PMX), alone or combined with biochemical inhibitors of PDE5, 8, 9, or 10, against squamous and non-squamous NCSLC cells. Genomic alterations to PDE genes (PDEmut) or PDE biochemical inhibition (PDEi) can sensitize NSCLC to PMX in vitro (observed in 50% NSCLC evaluated). The synergistic activity of PDEi with PMX required microdosing of the anti-folate drug. As single agents, none of the PDEis evaluated have anti-tumor activity. PDE biochemical inhibitors, targeting either cAMP or cGMP signaling (or both), resulted in significant cross-modulation of downstream pathways. The use of PDEi may present a new strategy to overcome PMX resistance of PDEwt NSCLC tumors but comes with important caveats, including the use of subtherapeutic PMX doses.