Frequent overexpression of the c-kit protein in large cell neuroendocrine carcinoma of the lung

Abstract

Overexpression of receptor-type tyrosine kinases in various cancers is associated with an aggressive tumor phenotype and poor outcome, but their expression had never been evaluated in large cell neuroendocrine carcinoma (LCNEC) of the lung. In the present study, we investigated the expression of three receptor tyrosine kinases, epidermal growth factor receptor (EGFR), c-erbB-2, and c-kit protein, by comparing surgically resected 40 LCNECs with other neuroendocrine (NE) lung tumors: 9 typical carcinoids (TCs), 5 atypical carcinoids (ACs), and 13 small cell lung carcinomas (SCLCs). None of the NE lung tumors showed expression of EFGR or c-erbB-2, but c-kit was overexpressed in 55% of the LCNEC tumor cells and 46% of the SCLC tumor cells. None of the clinicopathologic factors in either the LCNEC or SCLC patients correlated with c-kit overexpression. The finding that c-kit expression in LCNEC is similar to its expression in SCLC suggests that inhibition of c-kit may be effective as a therapy targeting LCNEC as well as SCLC.

Introduction

Lung cancer is currently a major cancer throughout the world, and it is the most common cause of cancer mortality worldwide [1]. The revised WHO classification of lung cancer published in 1999 classifies neuroendocrine (NE) tumors into four major histological categories: low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), and high-grade large cell NE carcinoma (LCNEC) and small cell lung carcinoma (SCLC). LCNEC is classified as a non-small cell lung carcinoma (NSCLC), but it is classified as a high-grade NE carcinoma, the same as SCLC is [1]. LCNEC is an aggressive malignancy with an outcome approaching the dismal outlook for SCLC [2], which differs from NSCLC clinicopathologically in several ways. The optimal therapy for LCNEC remains to be defined [3].

Receptor-tyrosine kinases initiate specific intracellular signaling pathways in response to binding of extracellular growth factors and are known to play an important role in regulating normal and cancer cell growth and differentiation [4], [5]. Overexpression of receptor-type tyrosine kinases is associated with an aggressive tumor phenotype and poor outcome of various cancers, including breast cancer [6], gastrointestinal stromal tumors (GISTs) [7] [8], and cervical carcinoma [9]. They have also been shown to be overexpressed or amplified in a number of human carcinomas, and epidermal growth factor receptor (EGFR) has been reported to be overexpressed in 40 to 81% of NSCLCs [10]. Receptor-tyrosine kinase inhibitors with relative specificity for EGFR, including ZD1839 (‘Iressa’, Astra Zeneca, UK), inhibit the growth of EGFR-positive human lung cancers both in vitro [11] and in vivo [12]. A member of the erbB family of receptor tyrosine kinases, c-erbB-2, has been reported to be overexpressed in 30 to 35% of NSCLCs [10], and a humanized anti-c-erbB-2 monoclonal antibody, trastuzumab (Herceptin; Genentech, Inc., South San Francisco, CA), inhibits the growth of human NSCLC cell lines that overexpress c-erbB-2 [13].

Another tyrosine kinase, c-kit oncoprotein, is expressed in a variety of human tumors, including mastocytosis [14], germ cell tumors [15], GIST [16], and SCLC [17]. A tyrosine kinase inhibitor, STI 571 (formerly known as CGP57148B, Novartis Pharmaceuticals), was initially developed as an ATP competitive inhibitor of Abl protein kinase [18] and has been shown to inhibit not only chimeric BCR/ABL kinase activity, growth of chronic myelogenous leukemia, and viability of cells transformed by Abl oncogenes [19], but c-kit kinase activity, which is frequently overexpressed in GIST. The results of a phase I study of STI 571 in metastatic GISTs overexpressing c-kit have provided evidence for a role of c-kit in the proliferation of GISTs [20], and STI 571 has been reported to inhibit the growth of c-kit-expressing SCLC cell lines [21].

Based on a new strategy for cancer treatment, specific growth factor signal abnormalities in tumors may serve as targets of new pharmacological therapies. In contrast to SCLC, the optimal growth factor target has never been investigated or evaluated in LCNEC. The present study was undertaken to investigate the pattern of expression of EGFR, c-rbB-2, and c-kit in LCNEC in comparison with other NE tumors, including TC, AC, and SCLC, in an attempt to identify a new molecular target for the treatment of LCNEC.