HER3 and c-Met Co-Expression in Non-Small and Small Cell Lung Cancers
M Li, J Song, L Faoro, M Tretiakova, R Salgia, T Krausz, AN Husain. University of Chicago, Chicago
Background: Gifitinib/erlotinib, tyrosine kinase inhibitors (TKIs) which target the epdidermal growth factor receptor (EGFR) pathway, are effective in the treatment of non-small cell lung cancers (NSCLC) harboring somatic mutations in EGFR. However, despite an initial response, most EGFR mutant NSCLCs ultimately become resistant to these agents. The persistent phosphorylation of HER3 and c-Met amplification are important mechanisms of this acquired resistance, through the PI3K/Akt pathway. To overcome this, ongoing clinical trials are evaluating irreversible EGFR inhibitors alone or in combination with c-Met inhibitors. Here we conducted the first large-scale study of HER3 and c-Met expression in EGFR TKI-naive NSCLC and small cell lung cancers (SCLC).
Design: With IRB approval, tumor tissue microarrays of 25 squamous cell carcinomas (SCC), 42 adenocarcinomas (AC), 34 SCLC, and 35 large cell lung carcinomas (LCLC), with at least 2 cores from each case were immunohistochemically stained for HER3 and c-Met. Among them, 60 cases (23 SCC, 19 AC, 7 SCLC and 11 LCLC) had cores from both tumor center and advancing edge. In addition, a separate set of 16 metastatic tumors (4 SCC, 7 AC and 5 LCLC) with cores from both primary and lymph node metastasis were studied. The staining intensity was scored as: 0 (negative), 1+ (weak), or 2+ (strong).
Results: Both HER3 and c-Met showed a predominantly cytoplasmic staining and were expressed in the majority of cases, except for c-Met in SCC (Table 1). HER3 expression was strongest in SCC and SCLC, and was weakest in LCLC (p<0.01). C-Met was strongest in AC and weakest in SCC (p<0.01). The two markers were frequently co-expressed (SCC 48%, AC 95%, SCLC 76%, LCLC 86%). There was no significant difference in the expression level between tumor center and advancing edge, or between primary tumor and metastasis.
Table 1. Expression of HER3 and c-Met in NSCLC and SCLC.
Conclusions: This study demonstrates that HER3 and c-Met are co-expressed in the majority of EGFR TKI-naive NSCLC and SCLC. Our data supports the potential use of combined TKIs in naive NSCLC to avoid drug resistance. This study is the first to show that both HER3 and c-Met are co-expressed in the majority of SCLC (76%), suggesting that SCLC patients with both HER3 and c-Met abnormalities may benefit from combined regimens targeting these two genes.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 227, Tuesday Afternoon