Small cell lung cancer (SCLC) is an aggressive illness, for which cytotoxic chemotherapy appears to have plateaued. A number of abnormal genetic events have been identified in SCLC, including overexpression of several receptor tyrosine kinases (RTKs). RTKs are proto-oncogenes, and are key regulators for cell growth, differentiation, survival or motility. The role of RTKs has just begun to be identified in SCLC and we would like to propose to study c-Met in particular. SCLC cell growth can be influenced in a paracrine fashion with receptors such as c-Met and its ligand hepatocyte growth factor (HGF) produced by stromal cells, c- Met/HGF has been shown to be involved in proliferation, cell motility and migration, invasion, angiogenesis and metastasis in other solid tumors. There are a considerable number of mutations identified for c-Met in a variety of solid tumors, however none to date have been investigated in lung cancer specimens. The best characterized mutations are in hereditary renal cell carcinoma and the mutations are mainly in the tyrosine kinase domains. We propose to study the role of c-Met in SCLC. Utilizing 10 separate SCLC cell lines and 32 paired tumor specimens from patients with SCLC, we have identified novel mutations in c-Met (3/10 cell lines and 4/32 tumor tissue samples), especially in the juxtamembrane (JM) domain. The specific JM domain mutations in c-Met have not been previously described in SCLC or other tumors. We have recently also shown the c-Met/HGF pathway to be functional in SCLC cell lines, with dramatic effects on cell motility and migration. The goal of this proposal is to determine the role of the mutations of c-Met in SCLC. Also, we will study the implications of c-Met/HGF activation in SCLC with emphasis on cell motility and migration as a reflection of metastasis of SCLC. Finally, we will utilize small molecule inhibitors that we have obtained of c- Met to determine if this pathway can be therapeutically targeted in SCLC with the eventual goal of bringing these molecules to clinical trials. ? ?
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