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Functional Expression and Mutations of c-Met and Its Therapeutic Inhibition with SU11274 and Small Interfering RNA in Non–Small Cell Lung Cancer

¹ Section of Hematology/Oncology, Department of Medicine, and ² Department of Pathology, University of Chicago Medical Center, Pritzker School of Medicine, Chicago, Illinois; Departments of ³ Molecular Diagnostics and ⁴ Medical Oncology, Dana-Farber Cancer Institute, and ⁵ Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; ⁶ BioSource International, Inc., Camarillo, California; and ⁷ Research Pharmacology, Pfizer, Inc., San Diego, California

Requests for reprints: Ravi Salgia, Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center, Pritzker School of Medicine, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637. Phone: 773-702-4399; Fax: 773-834-1798; E-mail: rsalgia{at}medicine.bsd.uchicago.edu.

Non–small cell lung cancer (NSCLC) is a difficult disease to treat. The c-Met receptor is an attractive potential target for novel therapeutic inhibition in human cancers. We provide strong evidence that c-Met is overexpressed, activated, and sometimes mutated in NSCLC cell lines and tumor tissues. Expression of c-Met was found in all (100%) of the NSCLC tumor tissues examined (n = 23) and most (89%) of the cell lines (n = 9). Sixty-one percent of tumor tissues strongly expressed total c-Met, especially adenocarcinoma (67%). Specific expression of phospho-Met (p-Met) [Y1003] and [Y1230/1234/1235] was seen by immunohistochemistry. p-Met expression was preferentially observed at the NSCLC tumor invasive fronts. c-Met alterations were identified within the semaphorin domain (E168D, L299F, S323G, and N375S) and the juxtamembrane domain (R988C, R988C + T1010I, S1058P, and alternative splice product skipping entire juxtamembrane domain) of a NSCLC cell line and adenocarcinoma tissues. We validated c-Met as potential therapeutic target using small interfering RNA down-regulation of the receptor expression by 50% to 60% in NSCLC cells. This led to inhibition of p-Met and phospho-AKT and up to 57.1 ± 7.2% cell viability inhibition at 72 hours. The selective small molecule inhibitor of c-Met SU11274 inhibited cell viability in c-Met-expressing NSCLC cells. SU11274 also abrogated hepatocyte growth factor–induced phosphorylation of c-Met and its downstream signaling. Here, we provide first direct evidence by small interfering RNA targeting and small molecule inhibitor that c-Met is important in NSCLC biology and biochemistry. These results indicate that c-Met inhibition will be an important therapeutic strategy against NSCLC to improve its clinical outcome.

Key Words: c-Met • HGF • kinase inhibitor • phosphorylation • non–small cell lung cancer • targeted therapy

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