Abstract 281: Phosphodiesterase 8/9 inhibition to sensitize squamous non-small cell lung cancer (NSCLC) to pemetrexed (PMX): A double-edge strategy

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (7_Supplement), p.281-281
• Main Authors: Foureau, Anna V. Ivanina, Foureau, David M., Farhangfar, Carol J., Mileham, Kathryn F.
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-281

Introduction. Phosphosidesterases (PDE) are key regulators of cyclic nucleotide (cAMP/cGMP) signaling regulating many cellular processes including cell proliferation, growth arrest and apoptosis. In squamous NSCLC (SCC), PDE inhibitors (PDEi) have shown anti-tumor activity both as single agent and in combination with chemotherapy. A strong putative synergistic mechanistic activity exists between pemetrexed (PMX) and PDEi through cAMP/Protein kinase A (PKA) and cGMP/Protein Kinase G signaling. We therefore thought to investigate whether SCC, classically resistance to PMX can be sensitized to the drug through PDE inhibition. Methods. Whole exome sequencing and survival data from TCGA was surveyed to identify PDEs most closely associated with clinical outcome in NSCLC. Whole exome sequencing data from GEmiCCL database were used to select SCC cell lines with unaltered PDE genes. Two SCC cell lines (H226, H1703) were evaluated for viability (WST8 assay), proliferation and apoptosis (Apo-Tox-Glo assay) after treatment with PMX with or without sildenafil citrate, PF-04671536 or PF-04447943 (PDE5i, PDE8i and PDE9i respectively). PDE expression was quantified by qPCR and Western Blot (WB). PDE activity and downstream signaling was quantified by measuring PKA/PKG target activation (PKA/pVASP157, PKG/pVAP239). Results. Presence of function altering mutations in PDE8 (cAMP/PKA signaling) and PDE9 (cGMP/PKG signaling) improved NSCLC overall survival (P