Abstract 4357: Polyisoprenylated methylated protein methyl esterase as a potential therapeutic target and biomarker in lung cancer.

Abstract

Abstract PURPOSE: Excessive epidermal growth factor receptor (EGFR) signaling and/or hyperactivities of polyisoprenylated monomeric G-proteins of the Ras superfamily are frequently associated with various human cancers including lung cancer. While mutations or overexpression of these proteins are responsible for their tumorigenic effects, secondary modifications of the monomeric G-proteins involving polyisoprenylation and eventual methylation are required for their normal as well as the pathological activities. Despite the use of anti-EGFR targeted therapies, prognosis is still poor for patients whose tumors harbor the defective receptor. The need to find novel biomarkers for early/companion diagnosis and targets for the development of novel therapies remains strong. Since polyisoprenylated methylated protein methyl esterase (PMPMEase) is a critical enzyme of the polyisoprenylation pathway whose inhibition causes cancer cell death, the objective was to determine whether it is overexpressed and/or hyperactive in lung cancers in which case, it might serve as a possible diagnostic biomarker or drug target. METHODS: Tissue microarrays (TMAs) consisting of 416 cores from 416 separate normal lung and lung cancer cases were analyzed for PMPMEase expression. Also, PMPMEase activities in fresh frozen lung cancer tissues were determined. PMPMEase expression and activities in normal lung fibroblasts (WI-38) as well as lung cancer A549 and H460 cells were also determined. The effect of specific PMPMEase inhibition with L-28 on cell viability was also tested. RESULTS: Significantly more intense PMPMEase immunoreactivity was observed in 88.3% of the 416 cases in the lung cancer compared to the normal controls (p < 0.0001). The mean scores ± SEM were 118.8±7.7 (normal), 232.1±25.1 (small-cell lung carcinomas), 352.1±9.4 (squamous cell carcinomas), 311.7±9.8 (adenocarcinomas), 350.0±24.2 (papillary adenocarcinomas), 334.7±30.1 (adenosquamous carcinomas), 321.9±39.7 (bronchioloalveolar carcinomas), and 331.3±85.0 (large-cell carcinomas). PMPMEase was significantly more active in five of the ten lung cancer cases compared to normal adjacent tissues (p < 0.001). The specific PMPMEase activity in A549 (5.2 ± 0.10 mmol/h/mg of protein) and H460 (4.8 ± 0.05 mmol/h/mg of protein) cells was 1.6- and 1.5-fold higher than in WI-38 cells (3.2 ± 0.04 mmol/h/mg of protein), respectively. Exposure of the cells to L-28, led to lung cancer cell death, with EC50 of 8.5 x 10-6 M for A549 and 2.8 x 10-5 M for H460 cells. CONCLUSION: These results implicate PMPMEase overexpression and hyperactivity in lung cancer progression, implying that PMPMEase could serve as a marker for diagnosis and target for lung cancer therapy. Citation Format: Felix Amissah, Randolph Duverna, Byron J. Aguilar, Rosemary A. Poku, Lamango S. Lamango. Polyisoprenylated methylated protein methyl esterase as a potential therapeutic target and biomarker in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4357. doi:10.1158/1538-7445.AM2013-4357