Expression profiling of receptor tyrosine kinases

Authors: Yuki Matsumura Shigeki Umemura Genichiro Ishii Koji Tsuta Shingo Matsumoto Keiju Aokage Tomoyuki Hishida Junji Yoshida Yuichiro Ohe Hiroyuki Suzuki Atsushi Ochiai Koichi Goto Kanji Nagai Katsuya Tsuchihara

Publish Date: 2015/05/20

Volume: 141, Issue: 12, Pages: 2159-2170

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Abstract

As the comprehensive genomic analysis of small cell lung cancer SCLC progresses novel treatments for this disease need to be explored With attention to the direct connection between the receptor tyrosine kinases RTKs of tumor cells and the pharmacological effects of specific inhibitors we systematically assessed the RTK expressions of highgrade neuroendocrine carcinomas of the lung HGNECs including SCLC and large cell neuroendocrine carcinoma LCNECFiftyone LCNEC and 61 SCLC patients who underwent surgical resection were enrolled in this research As a control group 202 patients with adenocarcinomas ADCs and 122 patients with squamous cell carcinomas SQCCs were also analyzed All the tumors were stained with antibodies for 10 RTKs cKit EGFR IGF1R KDR ERBB2 FGFR1 cMet ALK RET and ROS1The LCNEC and SCLC patients exhibited similar clinicopathological characteristics The IHC scores for each RTK were almost equivalent between the LCNEC and SCLC groups but they were significantly different from those of the ADC or SQCC groups In particular cKit was the only RTK that was remarkably expressed in both LCNECs and SCLCs On the other hand about 20  of the HGNEC tumors exhibited strongly positive RTK expression and this rate was similar to those for the ADC and SQCC tumors Intriguingly strongly positive RTKs were almost mutually exclusive in individual tumorsLarge cell neuroendocrine carcinoma LCNEC is distinguished from small cell lung carcinoma SCLC based on its histological criteria that is a larger cell size abundant cytoplasm prominent nucleoli vesicular nuclei or coarse chromatin and a polygonal rather than a fusiform shape Battafarano et al 2005 Despite these differences LCNEC and SCLC share many similarities in terms of not only immunohistochemistry but also clinical characteristics Gupta et al 2004 Asamura et al 2006 Fernandez and Battafarano 2006 Gollard et al 2010 Nakachi et al 2010 Dobashi et al 2011 Li et al 2012 Peifer et al 2012 Rudin et al 2012 Sun et al 2012 Consequently these lesions are often grouped together as highgrade neuroendocrine carcinoma HGNEC LCNEC also shares genetic alterations that are commonly seen in SCLCs such as TP53 RB1 and EP300 Jones et al 2004 Peifer et al 2012 Rudin et al 2012 CLCGPNGM 2013 suggesting a genetic similarity to SCLC However little is known about the differences in the protein expression profiles between these two histological typesIn addition only fragmented information on therapeutically relevant gene alterations is available for HGNECs Two reports regarding integrative genomic analyses of SCLC have shown that transcriptional deregulation for example via RB1 SOX2 and MYC family members and chromatin modifiers might have a role in its biologyPeifer et al 2012 Rudin et al 2012 To date however attempts to develop targeted therapies for these transcriptional deregulations have had limited success Recently we performed wholeexome sequencing of 51 Asian SCLC patients and demonstrated that the SCLC genome possessed distinguishable genetic features in the PI3K/AKT/mTOR pathway Umemura et al 2014 In this report both gene mutations and copy number variations were analyzed and genetic alterations in various targetable wellknown receptor tyrosine kinase RTK genes were detected but these variations were not correlated with the genetic changes in the PI3K/AKT/mTOR pathway and their functional roles have remained unclearAs already known RTKs are the initial signaling gate on the cell membrane Given their pivotal roles in tumor initiation and progression RTKs have become one of the most prominent target families for drug development IASLC 2009 Umemura et al 2014 Therefore in the present study we analyzed the protein expressions of the major RTKs of the HGNEC tumors which we examined using wholeexome sequencing and compared them with those of adenocarcinoma ADC and squamous cell carcinoma SQCC to identify biologically distinctive alterations in HGNECs

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