Abstract 4372: Phosphodiesterase 10A inhibition suppresses lung tumor cell growth by activating PKG to inhibit ras and Wnt signaling

We recently reported that phosphodiesterase 10A (PDE10) is overexpressed in colon tumors and essential for colon tumor cell growth (Li et al., Oncogene 2014), but a role in lung cancer has not been well studied. Human non-small cell lung cancer (NSCLC) cell lines were found to express appreciably higher PDE10 levels compared with normal airway epithelial cells, while silencing of PDE10 expression with siRNA or inhibition of PDE10 activity with small molecule inhibitors selectively inhibits NSCLC cell growth. Here we study the mechanism by which PDE10 inhibitors suppress NSCLC cell growth. At concentrations effective for inhibiting NSCLC cell growth, the PDE10 inhibitor, PQ10 rapidly increases intracellular cGMP levels as determined by a luminescence biosensor assay. Within the same concentration range and time period, PQ10 activates PKA and PKG, demonstrated by an increase in phosphorylation of the substrate, VASP at Ser157 and Ser239, respectively. Under the same conditions, PQ10 suppresses the phosphorylation of Erk1/2 (Thr202/Tyr204), MEK1/2 (Ser217/Ser221) and down-stream p90RSK (Ser380). Similarly, PQ10 increases the phosphorylation of β-catenin at Ser552, but showed no effect on phospho-Ser675 levels. After longer durations of treatment, PQ10 reduces β-catenin levels, as well as proteins that are regulated by β-catenin-dependent TCF/LEF-transcriptional activity, such as survivin and cyclin D1. These effects were mimicked by a novel structurally unrelated PDE10 inhibitor, ADT-020 that selectively inhibits the growth of NSCLC cells and increases cGMP levels in a manner similar to PQ10. ADT-020 also activates PKG in NSCLC cells demonstrated by higher phospho-Ser239 VASP levels and lower β-catenin and survivin levels. These observations suggest that PDE10 inhibition and activation of PKG can simultaneously suppress ras and Wnt signaling that are essential for lung tumor cell growth. Supported by NIH grants 1R01CA155638 and 1R01CA131378 (Piazza). Citation Format: Bing Zhu, Kevin Lee, Joshua Canzoneri, Veronica Ramirez-Alcantara, Sara Sigler, Bernard Gary, Ethan Butler, Adam Keeton, Xi Chen, Michael Boyd, Gary Piazza. Phosphodiesterase 10A inhibition suppresses lung tumor cell growth by activating PKG to inhibit ras and Wnt signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4372. doi:10.1158/1538-7445.AM2015-4372