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

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 Scrima1,2✉, 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 Zoppoli2✉, Giuseppe Viglietto2✉

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.

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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. Available from http://www.jcancer.org/v08p0227.htm

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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.