EGFR/c-Met and mTOR signaling are predictors of survival in non-small cell lung cancer

Zachary D Crees; Caleb Shearrow; Leo Lin; Jennifer Girard; Kavin Arasi; Aayush Bhoraskar; Joseph Berei; Adam Eckburg; Austin D Anderson; Christian Garcia; Ariana Munger; Sunil Palani; Thomas J Smith; Shylendra B Sreenivassappa; Connie Vitali; Odile David; Neelu Puri

doi:10.1177/1758835920953731

EGFR/c-Met and mTOR signaling are predictors of survival in non-small cell lung cancer

Ther Adv Med Oncol. 2020 Sep 14:12:1758835920953731. doi: 10.1177/1758835920953731. eCollection 2020.

Authors

Zachary D Crees¹, Caleb Shearrow¹, Leo Lin¹, Jennifer Girard¹, Kavin Arasi¹, Aayush Bhoraskar¹, Joseph Berei¹, Adam Eckburg¹, Austin D Anderson¹, Christian Garcia¹, Ariana Munger¹, Sunil Palani¹, Thomas J Smith², Shylendra B Sreenivassappa³, Connie Vitali⁴, Odile David⁵, Neelu Puri⁶

Affiliations

¹ Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, IL, USA.
² College of Education, Northern Illinois University, Dekalb, IL, USA.
³ Department of Hematology/Oncology, OSF Saint Anthony Medical Center, Rockford, IL, USA.
⁴ Department of Pathology, University of Illinois College of Medicine at Rockford IL, USA.
⁵ Department of Pathology, University of Illinois College of Medicine at Chicago, IL, USA.
⁶ Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, 1601 Parkview Avenue, Room Number E-632, Rockford, IL 61107, USA.

Abstract

Background: EGFR/c-Met activation/amplification and co-expression, mTOR upregulation/activation, and Akt/Wnt signaling upregulation have been individually associated with more aggressive disease and characterized as potential prognostic markers for lung cancer patients.

Methods: Tumors obtained from 109 participants with stage I-IV non-small cell lung cancer (NSCLC) were studied for EGFR/c-Met co-localization as well as for total and active forms of EGFR, c-Met, mTOR, S6K, beta-catenin, and Axin2. Slides were graded by two independent blinded pathologists using a validated scoring system. Protein expression profile correlations were assessed using Pearson correlation and Spearman's rho. Prognosis was assessed using Kaplan-Meier analysis.

Results: Protein expression profile analysis revealed significant correlations between EGFR/p-EGFR (p = 0.0412) and p-mTOR/S6K (p = 0.0044). Co-localization of p-EGFR/p-c-Met was associated with increased p-mTOR (p = 0.0006), S6K (p = 0.0018), and p-S6K (p < 0.0001) expression. In contrast, active beta-catenin was not positively correlated with EGFR/c-Met nor any activated proteins. Axin2, a negative regulator of the Wnt pathway, was correlated with EGFR, p-EGFR, p-mTOR, p-S6K, EGFR/c-Met co-localization, and p-EGFR/p-c-Met co-localization (all p-values <0.03). Kaplan-Meier analysis revealed shorter median survival in participants with high expression of Axin2, total beta-catenin, total/p-S6K, total/p-mTOR, EGFR, and EGFR/c-Met co-localization compared with low expression. After controlling for stage of disease at diagnosis, subjects with late-stage disease demonstrated shorter median survival when exhibiting high co-expression of EGFR/c-Met (8.1 month versus 22.3 month, p = 0.050), mTOR (6.7 month versus 22.3 month, p = 0.002), and p-mTOR (8.1 month versus 25.4 month, p = 0.004) compared with low levels.

Conclusions: These findings suggest that increased EGFR/c-Met signaling is correlated with upregulated mTOR/S6K signaling, which may in turn be associated with shorter median survival in late-stage NSCLC.

Keywords: EGFR/c-Met; biomarker; mTOR; non-small cell lung cancer; prognosis.

Grants and funding

R21 CA158965/CA/NCI NIH HHS/United States