Abstract 4755: Correlation of expression of EGFR, cMET and mTOR signaling pathway proteins with each other and their impact on prognosis in non-small cell lung cancer patients
Authors: Crees Zachary , Shearrow Caleb , Lin Leo , Girard Jennifer , Arasi Kavin , Bhoraskar Aayush , Nowak Andrew , Sheu Bonnie , Chhabra Gagan , Sreenivassappa Shylendra , Vitali Connie , David Odile , Puri Neelu 
Published: July 2016

Abstract
NSCLC tumors acquire resistance to EGFR-TKIs, and studies have suggested that co-localization of c-MET and EGFR may be a modality of acquired resistance. Upregulation of alternative signaling pathways such as Wnt or mTOR have been shown to be associated with poor prognosis and are a potential mechanism of resistance. This study aims at examining these signaling pathways and EGFR/c-MET co-expression in 100 patients with stage I-IV NSCLC. We have data on 50 patients, and are working on the remaining samples. Tumor tissue from biopsies or resections have been obtained with IRB approval, processed, sectioned, and mounted on microscope slides. Total and active forms of EGFR, c-MET, mTOR, S6K, beta-catenin, and Axin2 were detected using singleplex or multiplex IHC staining procedures, and stains were graded by an independent pathologist using a validated scoring system. We selected Stage IV NSCLC (n = 32) patients to correlate EGFR/c-MET expression with overall survival, and analyzed them for months to mortality based on high or low EGFR expression. Patients with high EGFR expression (n = 16) showed lower overall survival compared to those with low EGFR expression (n = 16). Expression of c-MET is linked to decreased survival in Stage IV NSCLC patients (n = 4). Patients with EGFR/c-MET co-localization (n = 19) showed decreased overall survival compared to patients without EGFR/c-MET co-localization (n = 9). Elevated mTOR and p-mTOR are associated with worse prognosis in Stage IV NSCLC patients. Patients categorized with either low mTOR expression (n = 10) or high mTOR expression (n = 19) showed increased mortality with high mTOR expression (5.9 months) compared to patients with low mTOR expression (13.5 months). A similar trend was seen in patients with either low (n = 4, 7.5 months) or high (n = 24, 15.9 months) p-mTOR expression. Patients with low beta-catenin expression (n = 4) showed improved survival in comparison to patients with high beta-catenin expression (n = 18), 9.4 months vs 6.3 months, respectively. To determine correlations in expression of these proteins we found that EGFR/c-MET co-expression is inversely correlated with active beta-catenin and directly correlated with a negative regulator of beta-catenin, Axin-2 suggesting EGFR/c-MET co-expression is associated with a downregulation of Wnt activity. In contrast, elevated EGFR/c-MET co-expression and co-activation is statistically significantly correlated with elevated mTOR-S6K expression and activation suggesting EGFR/c-MET co-expression is associated with an upregulation of the mTOR pathway activity. Elevated mTOR pathway activation at the time of diagnosis is statistically significantly associated with poor prognosis in patients with stage IV NSCLC. These preliminary results suggest that mTOR inhibition therapy in addition to EGFR/c-MET inhibition therapies may be beneficial in this population.
Citation Format: Zachary Crees, Caleb Shearrow, Leo Lin, Jennifer Girard, Kavin Arasi, Aayush Bhoraskar, Andrew Nowak, Bonnie Sheu, Gagan Chhabra, Shylendra Sreenivassappa, Connie Vitali, Odile David, Neelu Puri. Correlation of expression of EGFR, cMET and mTOR signaling pathway proteins with each other and their impact on prognosis in non-small cell lung cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4755.