Abstract 2400: Differential phosphorylation of signaling targets as a function of RAS mutation status and tumor histology in non-small cell lung cancer.

Abstract

Abstract Background: While the importance of RAS and mTOR signaling pathways in non-small cell lung cancer (NSCLC) is well known, the activation status of key components in the pathway as a function of histology and oncogene mutation status has been not completely described. The purpose of this study is to investigate phosphorylation status of signal transduction pathway members and to elucidate their prognostic significance in relation to adenocarcinoma and squamous cell carcinoma. Methods: Phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK), MEK 1 and 2 (pMEK), and mammalian target of rapamycin (pmTOR) were immunohistochemically examined using tissue microarray samples of 269 surgically resected primary NSCLC. Thyroid transcription factor-1 (TTF-1) expression and mutation status of EGFR and KRAS were also evaluated. The relationships between 5-year progression free survival (PFS) and phospho-protein expression were investigated by univariate analyses of log-rank test and multivariate analyses using Cox regression model. Results: A total of 98 adenocarcinomas and 134 squamous cell carcinomas were included in the analyses. In adenocarcinoma, pERK expression was significantly related to pMEK (P = 0.001), pmTOR (P < 0.001), and TTF-1 (P = 0.013) expression. In squamous cell carcinoma, pERK expression was significantly related to pMEK (P < 0.001) expression. EGFR or KRAS mutations were significantly associated with TTF-1 expression (P = 0.014) in adenocarcinoma. However, EGFR and KRAS mutation status were not significantly associated with pERK, pMEK, and pmTOR expressions in adenocarcinoma. By univariate analyses, high pERK expression was associated with better 5-year PFS (P = 0.018) in adenocarcinoma and high pMEK expression was associated with worse 5-year PFS (P = 0.043) in squamous cell carcinoma. In multivariate analyses, pERK (P = 0.040) and pMEK (P = 0.048) expression were independent prognostic factors. Conclusions: There were different patterns of phospho-protein expression in adenocarcinoma and squamous cell carcinoma. pERK expression was a good prognostic factor only in adenocarcinoma and pMEK expression was a poor prognostic factor only in lung squamous cell carcinoma. Citation Format: Sang-Won Um, Jingxiang Chen, Carrie Lee, Norman E. Sharpless, Patrick J. Roberts, D. Neil Hayes. Differential phosphorylation of signaling targets as a function of RAS mutation status and tumor histology in non-small cell 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 2400. doi:10.1158/1538-7445.AM2013-2400