Details

Autor(en) / Beteiligte

• MA, Patrick C
• JAGADEESWARAN, Ramasamy
• RICHARDS, William
• SUGARBAKER, David
• HUSAIN, Aliya N
• CHRISTENSEN, James G
• SALGIA, Ravi
• JAGADEESH, Simha
• TRETIAKOVA, Maria S
• NALLASURA, Vidya
• FOX, Edward A
• HANSEN, Mark
• SCHAEFER, Erik
• NAOKI, Katsuhiko
• LADER, Alan

Titel

Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer

Ist Teil von

• Cancer research (Chicago, Ill.), 2005-02, Vol.65 (4), p.1479-1488

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2005

Link zum Volltext

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• 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.