Abstract
Small-cell lung cancer (SCLC) is one of the most aggressive lung tumors. The majority of patients with SCLC are diagnosed at an advanced stage. This tumor type is highly sensitive to chemo-radiation treatment, with very high response rates, but invariably relapses. At this time, treatment options are still limited and the prognosis of these patients is poor. A better knowledge of the molecular biology of SCLC allowed us to identify potential druggable targets. Among these, the MET/HGF axis seems to be one of the most aberrant signaling pathways involved in SCLC invasiveness and progression. In this review, we describe briefly all recent literature on the different molecular profiling in SCLC; in particular, we discuss the specific alterations involving c-MET gene and their implications as a potential target in SCLC.
Highlights
Lung cancer remains the most common cause of cancer-related death worldwide [1]
There are different strategies developed to inhibit aberrant c-MET/hepatocyte growth factor (HGF) signaling pathway, including antibodies directed against HGF, c-MET receptor or decoy-MET, and small molecule directed against MET receptor tyrosine kinase domain or against downstream signaling modulators
Different studies showed that the presence of MET activation in MET-mutant Small-cell lung cancer (SCLC) cell lines was predictive of poor outcome and the use of PHA-665752, a selective c-MET inhibitor, inhibited colony formation and invasiveness [47]
Summary
Lung cancer remains the most common cause of cancer-related death worldwide [1]. Small-cell lung cancer (SCLC) accounts for 12%–15% of all lung cancers. Upon binding HGF/SF, MET receptor dimerizes resulting in the activation of tyrosine kinase domain through a process of trans-phosphorylation of the two tyrosine residues Y1234 and Y1235 and, in turn, of two docking tyrosines (Y1349 and Y1356) This process leads to the recruitment of several adaptor proteins (Gab and Grb2), which in turn activate different intracellular signaling pathways (RAS-RAF-MEK-ERK and PI3K-AKT cascades, the nuclear factor-kB complex and STAT3), responsible for driving proliferation, cell survival, morphogenesis, cell scattering, migration and invasiveness [27,28,29,30,31]. Other signaling co-receptors, such as EGFR, KRAS, plexins B, integrin and CD44v6, can cross-talk with the MET receptor, even in a HGF-independent manner, providing an alternative way to induce proliferation, survival, motility, angiogenesis and invasive growth [24]
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