Epidermal growth factor ligand/receptor loop and downstream signaling activation pattern in completely resected nonsmall cell lung cancer

Abstract

Background: In recent years, molecular insights shed light on the role of the epidermal growth factor receptor (EGFR) in nonsmall cell lung cancer (NSCLC), and new therapeutic agents, such as the EGFR tyrosine kinase inhibitors, were tested successfully, with responsiveness to those agents more likely in those patients with specific EGFR gene alterations. The objective of the current study was to investigate the protein profiles of EGFR, c-erb-B2, transforming growth factor alpha (TGF-alpha) (one of the EGFR ligands commonly expressed in NSCLC), and some downstream molecules, potentially to detect a subset of tumors with an activated autocrine loop that is responsible for higher intracellular signaling.

Methods: One hundred twelve consecutive patients with resected NSCLC were analyzed by immunohistochemistry for EGFR, the c-erb-B2 receptor, TGF-alpha, and pivotal molecules downstream from EGFR activation. Statistical correlations between the investigated molecular expression profiles and clinicopathologic data were performed.

Results: EGFR, c-erb-B2, TGF-alpha and downstream molecule expression, per se, was not correlated significantly with any clinicopathologic variables, with the exception of a significant correlation between squamous histology and EGFR and between adenocarcinoma and TGF-alpha. However, nearly 30% of NSCLCs demonstrated coexpression of both TGF-alpha and EGFR, and this molecular status was associated positively with a statistically significant expression of phosphatidylinositol 3 kinase and an inversely with mitogen-activated protein kinase expression.

Conclusions: The presence of a subgroup of NSCLCs with an activated autocrine loop may help to explain the mechanisms that lead to the relative ineffectiveness of the EGFR tyrosine kinase inhibitor and may support new clinical trials to define whether the subgroup of patients with these tumors reasonably may benefit from higher doses of such inhibitors or from the simultaneous inhibition of EGFR downstream signaling targets.