Aberrant Signaling through the HER2-ERK1/2 Pathway is Predictive of Reduced Disease-Free and Overall Survival in Early Stage Non-Small Cell Lung Cancer (NSCLC) Patients

Scrima, Marianna; Zito Marino, Federica; Oliveira, Duarte Mendes; Marinaro, Cinzia; La Mantia, Elvira; Rocco, Gaetano; De Marco, Carmela; Malanga, Donatella; De Rosa, Nicla; Rizzuto, Antonia; Botti, Gerardo; Franco, Renato; Zoppoli, Pietro; Viglietto, Giuseppe

doi:10.7150/jca.17093

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J Cancer 2017; 8(2):227-239. doi:10.7150/jca.17093 This issue Cite

Research Paper

Aberrant Signaling through the HER2-ERK1/2 Pathway is Predictive of Reduced Disease-Free and Overall Survival in Early Stage Non-Small Cell Lung Cancer (NSCLC) Patients

Marianna Scrima^1,2✉, Federica Zito Marino³, Duarte Mendes Oliveira², Cinzia Marinaro², Elvira La Mantia³, Gaetano Rocco³, Carmela De Marco², Donatella Malanga², Nicla De Rosa⁴, Antonia Rizzuto⁵, Gerardo Botti³, Renato Franco⁶, Pietro Zoppoli^2✉, Giuseppe Viglietto^2✉

1. Biogem scarl, Institute of Genetic Research, Ariano Irpino (AV), Italy.
2. Department of Experimental and Clinical Medicine, University “Magna Graecia”, Catanzaro, Italy.
3. Pathology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy.
4. Hospital “Monaldi-Cotugno-CTO”, Naples, Italy.
5. Department of Medical and Surgical Sciences, University “Magna Graecia” Medical School, Catanzaro, Italy
6. Pathology Unit, Second University of Naples, Italy.

✉ Corresponding author: Marianna Scrima, Biogem scarl, Institute of Genetic Research, Ariano Irpino (AV), Italy. email: marianna.scrimait. Pietro Zoppoli, Department of Experimental and Clinical Medicine, University Magna, Graecia, Catanzaro, More

Citation:

Scrima M, Zito Marino F, Oliveira DM, Marinaro C, La Mantia E, Rocco G, De Marco C, Malanga D, De Rosa N, Rizzuto A, Botti G, Franco R, Zoppoli P, Viglietto G. Aberrant Signaling through the HER2-ERK1/2 Pathway is Predictive of Reduced Disease-Free and Overall Survival in Early Stage Non-Small Cell Lung Cancer (NSCLC) Patients. J Cancer 2017; 8(2):227-239. doi:10.7150/jca.17093. https://www.jcancer.org/v08p0227.htm

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Abstract

Background: Purpose of this study was to evaluate the contribution of the Extracellular-regulated protein kinase (ERK)-1/2 pathway to oncogenic signaling elicited by the tyrosine kinase receptor HER2 in Non-Small Cell Lung Cancer (NSCLC) and to assess the prognostic value of these oncoproteins in NSCLC patients.

Methods: Immunohistochemistry was performed to determine expression and activation of HER2 and ERK1/2 (detected by phosphorylation of Y1248 and T202/Y204, respectively) using Tissue Micro Arrays (TMA) containing matched normal and neoplastic tissues from 132 NSCLC patients. Survival analysis was carried out using the Kaplan-Meier method. Univariate and multivariate analysis were used to evaluate the prognostic value of pERK1/2, pHER2 and a combination thereof with clinical-pathological parameters such as age, lymph node status (N), size (T), stage (TNM) and grade.

Results: We found that HER2 was overexpressed in 33/120 (27%) and activated in 41/114 (36%) cases; ERK1/2 was activated in 44/102 (43%) cases. A direct association was found between pERK1/2 and pHER2 (23/41; p=0.038). In addition, patients positive for pERK1/2 and for both pHER2 and pERK1/2 showed significantly worse overall survival (OS) and disease-free survival (DFS) compared with negative patients. Univariate and multivariate analysis of patients' survival revealed that positivity for pHER2-pERK1/2 and for pERK1/2 alone were independent prognostic factors of poor survival in NSCLC patients. In particular, this association was significantly important for DFS in stage I+II patients.

Conclusion: This study provides evidence that activated ERK1/2 and/or the combined activation of HER2 and ERK1/2 are good indicators of poor prognosis in NSCLC patients, not only in unselected patients but also in early stage disease.

Keywords: NSCLC, HER2, ERK1/2, Tissue Micro Array, survival.

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APA

Scrima, M., Zito Marino, F., Oliveira, D.M., Marinaro, C., La Mantia, E., Rocco, G., De Marco, C., Malanga, D., De Rosa, N., Rizzuto, A., Botti, G., Franco, R., Zoppoli, P., Viglietto, G. (2017). Aberrant Signaling through the HER2-ERK1/2 Pathway is Predictive of Reduced Disease-Free and Overall Survival in Early Stage Non-Small Cell Lung Cancer (NSCLC) Patients. Journal of Cancer, 8(2), 227-239. https://doi.org/10.7150/jca.17093.

ACS

Scrima, M.; Zito Marino, F.; Oliveira, D.M.; Marinaro, C.; La Mantia, E.; Rocco, G.; De Marco, C.; Malanga, D.; De Rosa, N.; Rizzuto, A.; Botti, G.; Franco, R.; Zoppoli, P.; Viglietto, G. Aberrant Signaling through the HER2-ERK1/2 Pathway is Predictive of Reduced Disease-Free and Overall Survival in Early Stage Non-Small Cell Lung Cancer (NSCLC) Patients. J. Cancer 2017, 8 (2), 227-239. DOI: 10.7150/jca.17093.

NLM

CSE

Scrima M, Zito Marino F, Oliveira DM, Marinaro C, La Mantia E, Rocco G, De Marco C, Malanga D, De Rosa N, Rizzuto A, Botti G, Franco R, Zoppoli P, Viglietto G. 2017. Aberrant Signaling through the HER2-ERK1/2 Pathway is Predictive of Reduced Disease-Free and Overall Survival in Early Stage Non-Small Cell Lung Cancer (NSCLC) Patients. J Cancer. 8(2):227-239.

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