Role of c-MET in lung cancer, malignant mesothelioma, and head and neck cancer

Abstract

9539 Background: c-MET is a potential therapeutic target with its aberrant signaling mediating invasive cellular program in cancers. Novel therapies are needed for lung cancer, mesothelioma and squamous cell carcinoma of head and neck (SCCHN) as their outcomes are poor despite standard therapy. Methods: We examined c-MET expression in cell lines and paraffin-embedded tumor tissues of lung cancer, mesothelioma and SCCHN using immunoblotting and immunohistochemistry (IHC) techniques. Activated-MET (pMET) was examined using phospho-MET antibodies in IHC in these tumor tissues, and using immunofluorescence (IF) in non-small cell lung cancer (NSCLC) A549 cells. Potential for targeted inhibition of c-MET was tested using small interfering RNA (siRNA) technique. siRNA-inhibition of c-MET expression was examined using immunoblotting, and the resultant inhibition of cell viability was studied using standard MTT assay. Results: There was varying c-MET expression in small cell lung cancer (SCLC) cell lines (N=10); and majority of the 9 NSCLC cell lines and 2 SCCHN cell lines had overexpression. In tumor tissues, c-MET expression was seen in 100% of thoracic malignancies (N=32). Strong expression was evident in 6/9 adenocarcinoma, 3/7 large cell, 3/7 squamous cell, and 3/5 carcinoid tumor). c-MET expression was also seen in tumor tissues of mesothelioma: 46% (N=13), and SCCHN: 54.5% (N=11). Activated pY1003-MET and pY1230/1234/1235-MET can also be demonstrated among all the tumor types. IF study showed that HGF dramatically increased pMET in A549 cells. c-MET expression was successfully inhibited using siRNA technique by >50% in the NSCLC A549 and mesothelioma H2373 cell lines. siRNA down-regulation of c-MET in A549 cells resulted in inhibition of viability (16.3±7.4% at 48hr; 57.1±7.2% at 72hr). Conclusions: c-MET is widely expressed in thoracic malignancies, mesothelioma and SCCHN with a potential role as novel therapeutic target. c-MET specific siRNA can successfully inhibit c-MET expression leading to significant inhibition of cell viability, and further inhibition strategies targeting the receptor will be sought for clinical applications. No significant financial relationships to disclose.