Ivanina Foureau Anna V, Foureau David M, McHale Cody C, Guo Fei, Farhangfar Carol J, Mileham Kathryn F
Translational Research, Levine Cancer Institute, Atrium Health, Charlotte, NC 28204, USA.
Immune Monitoring Core Laboratory, Levine Cancer Institute, Atrium Health, Charlotte, NC 28204, USA.
Cancers (Basel). 2024 Jul 6;16(13):2475. doi: 10.3390/cancers16132475.
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 (PDE) 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 PDE NSCLC tumors but comes with important caveats, including the use of subtherapeutic PMX doses.
磷酸二酯酶（PDEs）是环核苷酸信号传导的关键调节因子，控制着癌症的许多特征，并在非小细胞肺癌（NSCLC）对化疗的耐药性中发挥作用。我们评估了抗叶酸药物培美曲塞（PMX）单独或与PDE5、8、9或10的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（PDE）或PDE生化抑制（PDEi）可使NSCLC在体外对PMX敏感（在50%评估的NSCLC中观察到）。PDEi与PMX的协同活性需要微量使用抗叶酸药物。作为单一药物，所评估的PDEi均无抗肿瘤活性。靶向cAMP或cGMP信号传导（或两者）的PDE生化抑制剂导致下游途径的显著交叉调节。使用PDEi可能是克服PDE NSCLC肿瘤对PMX耐药性的一种新策略，但有重要的注意事项，包括使用低于治疗剂量的PMX。
