EGFR/c-Met and mTOR signaling are predictors of survival in non-small cell lung cancer
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...
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Series: | Therapeutic Advances in Medical Oncology |
Online Access: | https://doi.org/10.1177/1758835920953731 |
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doaj-8c227a1782da4256ae9803b9ba799ade2020-11-25T03:35:50ZengSAGE PublishingTherapeutic Advances in Medical Oncology1758-83592020-09-011210.1177/1758835920953731EGFR/c-Met and mTOR signaling are predictors of survival in non-small cell lung cancerZachary D CreesCaleb ShearrowLeo LinJennifer GirardKavin ArasiAayush BhoraskarJoseph BereiAdam EckburgAustin D. AndersonChristian GarciaAriana MungerSunil PalaniThomas J SmithShylendra B SreenivassappaConnie VitaliOdile DavidNeelu PuriBackground: 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.https://doi.org/10.1177/1758835920953731 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 EGFR/c-Met and mTOR signaling are predictors of survival in non-small cell lung cancer Therapeutic Advances in Medical Oncology |
author_facet |
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 |
author_sort |
Zachary D Crees |
title |
EGFR/c-Met and mTOR signaling are predictors of survival in non-small cell lung cancer |
title_short |
EGFR/c-Met and mTOR signaling are predictors of survival in non-small cell lung cancer |
title_full |
EGFR/c-Met and mTOR signaling are predictors of survival in non-small cell lung cancer |
title_fullStr |
EGFR/c-Met and mTOR signaling are predictors of survival in non-small cell lung cancer |
title_full_unstemmed |
EGFR/c-Met and mTOR signaling are predictors of survival in non-small cell lung cancer |
title_sort |
egfr/c-met and mtor signaling are predictors of survival in non-small cell lung cancer |
publisher |
SAGE Publishing |
series |
Therapeutic Advances in Medical Oncology |
issn |
1758-8359 |
publishDate |
2020-09-01 |
description |
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. |
url |
https://doi.org/10.1177/1758835920953731 |
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