Abstract 743: Expression profiles of EGFR, c-Met, and mTOR/Wnt alternative signaling pathway proteins in non-small cell lung cancer

Lung cancer is projected to be the number one cause of cancer mortality in the United States in 2014. Therapies such as tyrosine kinase inhibitors (TKIs) have been developed to treat non-small cell lung cancer (NSCLC), which accounts for 80-85% of all lung cancer cases. EGFR is a protein that is often targeted by these TKIs and several EGFR-TKIs have been approved for clinical use. However, NSCLC tumors almost inevitably acquire resistance to EGFR-TKIs, limiting drug efficacy. Previous studies have suggested that co-localization of c-MET and EGFR may be one possible modality of acquired resistance. Additionally, upregulation of alternative signaling pathways such as Wnt or mTOR have been shown to be associated with poor prognosis and have been described as potential mechanisms of resistance. Thus, this study examined these signaling pathways and the status of EGFR/c-Met co-expression in 42 patients with stage I-IV NSCLC. Tumor tissue from biopsy or resection was obtained with patient consent and IRB approval and was subsequently processed, sectioned, and mounted on microscope slides. Total and active forms of EGFR, c-Met, mTOR, S6K, β-Catenin, and Axin2 were detected using a singleplex or multiplexed immunohistochemistry staining procedure, and stains were graded by an independent pathologist using a validated scoring system. 65.9% of patients exhibited co-expression of EGFR and c-Met (n = 27) while 51.2% showed co-activation of the two markers (n = 21). Additionally, we observed EGFR/c-Met co-expression to have a statistically significant positive correlation with mTOR expression with a Spearman9s rho of 0.411 (p = 0.033), suggesting EGFR/c-Met co-expression may play a role in tumorigenesis possibly via regulation of the mTOR pathway. This notion is further supported by our finding that expression of pS6K, a downstream mTOR pathway protein, showed a strong positive correlation with EGFR expression with a Spearman9s rho of 0.504 (p = 0.001). In contrast, Wnt pathway protein active β-Catenin exhibits a negative correlation with EGFR expression while Axin2, a negative regulator of active β-Catenin, showed a positive correlation. Our findings indicate an inverse relationship between the two signaling pathways in NSCLC with increasing mTOR activation correlating with Wnt downregulation. Furthermore, EGFR expression may be associated with this relationship. Thus, we conclude that EGFR/c-Met co-expression as well as activation of the mTOR pathway may be involved in enhanced pathogenesis of NSCLC and possibly acquired resistance to EGFR-TKI therapy. Citation Format: Caleb Shearrow, Zachary Crees, Jennifer Girard, Kymberly Harrington, Kavin Arasi, Ceyda Bertram, Andrew Nowak, Leo Lin, Bonnie Sheu, Sunil Palani, Neelu Puri. Expression profiles of EGFR, c-Met, and mTOR/Wnt alternative signaling pathway proteins in non-small cell lung cancer. [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 743. doi:10.1158/1538-7445.AM2015-743