Abstract #LB-5: Increased expression of phospho-Met (Tyr1349) is found in Non-Small Cell Lung Cancer metastases

Growth factor receptors are important in lung cancer growth and progression and are potential targets for non-small cell lung cancer (NSCLC) therapy. c-Met, which is overexpressed in many cancers, is a tyrosine kinase receptor activated by binding to its ligand, hepatocyte growth factor (HGF). Receptor phosphorylation occurs at multiple tyrosines and leads to multiple biological responses including cell proliferation, motility, angiogenesis and morphogenesis. Our objective was an immunohistochemical study of c-Met and phospho-Met (p-Met)(Y1349) expression in clinical specimens of NSCLC. While expression of p-Met (Y1003) and (Y1230/1234/1235) has been reported in lung cancer, to our knowledge this is the first study of p-Met (Y1349) expression in NSCLC or other solid human tumors. Archived FFPE tissues from 52 lung cancer patients that underwent surgery at St. Elizabeth Medical Center between 1986 and 2000 were stained. Expression of c-Met and p-Met was evaluated semi-quantitatively for stain intensity and % of tissue stained. Histoscores (intensity X area) were calculated for cytoplasmic and nuclear stain. Data were analyzed by the Least Squares Means with the Tukey-Kramer adjustment. Survival was determined by Kaplan-Meier statistics. 31/32 (97%) primary adenocarcinoma (AdCa) specimens and 29/31 (94%) primary squamous cell carcinoma (SCC) specimens had cytoplasmic/membranous c-Met histoscores (HSC) of 0.9 - >1.8; 24/35 (69%) AdCa and 23/35 (66%) SCC had p-Met HSC of 0.45 - >1.8. In 52 patients, average C-Met HSC > 1 was marginally related to reduced survival (p = 0.0970). Except in bronchial epithelium, c-Met and p-Met (Y1349) expression was less in normal lung components compared to NSCLC; the average c-Met HSC in primary NCLC was significantly higher than the average c-Met HSC of all lung components including bronchial epithelium (1.95 + 0.10 vs. 1.59 + 0.06, p = 0.0050). c-Met HSC was similar in 66 specimens of primary NSCLC and 24 lymph node metastases (1.96 + 0.08 vs. 1.79 + 0.17, p = 0.2487); however p-Met (Y1349) HSC was significantly higher in lymph node metastases than primary NSCLC (1.04 + 0.14 vs. 0.71 + 0.08, p = 0.0351) or the average of all normal lung components (0.75 + 0.05, p = 0.0455). Median p-Met HSC in 40 patients with primary tumors without metastases was 0.468 vs. 1.052 in lymph node metastases from 12 patients. The p-Met (Y1249) nuclear histoscore was also significantly higher in lymph node metastases (0.32 + 0.12 vs. 0.11 + 0.03, p = 0.0038). We conclude that c-Met is overexpressed in both AdCa and SCC and is marginally related to survival, and that c-Met phosphorylation at tyrosine 1349 is increased in NSCLC metastases. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-5.