Bufexamac is a drug used as an anti inflammatory agent on the skin

by Selleckchem | Jan 21 2013

Recent research has demonstrated that the c-MET receptor tyrosine kinase and its ligand hepatocyte growth factor regulate a range of cellular functions.Under normal physiological conditions, HGFinduced c-MET tyrosine kinase activation is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, Bufexamac and ligand-activated receptor internalization and degradation.The Bufexamac importance of the HGF/c-MET pathway in the control of tissue homeostasis is supported by the well established protective activity of HGF in several degenerative diseases, including progressive nephropathies , liver cirrhosis and lung fibrosis.However, activated c-MET signaling caused by deregulation of normal cellular functions is clearly implicated in oncogenesis, leading to cell growth, proliferation, angiogenesis, invasion, survival, and metastasis.Activation of the c- MET signaling pathway can occur via activating mutations, overexpression of the kinase itself or its ligand HGF, or by autocrine, paracrine, or endocrine loop regulation.
c-MET as a Cabozantinib key target in oncological drug development Clinically, c-MET has gained considerable interest through its apparent deregulation by overexpression or mutation in various cancers, including non-small Cabozantinib cell lung cancer.Overexpression of c-MET, along with HGF, also appears indicative of an increased aggressiveness of tumors.The deregulation of c-MET identifies it as an Carfilzomib important therapeutic target in the development of future anticancer therapies.There is an increasing body of evidence that supports c-MET as a key target in oncology, for example through the development of small molecules or biological inhibitors.In addition, inhibition of c-MET affects downstream signal transduction with resulting biological consequences in tumor cells.The mutation or gene amplification of MET in Cabazitaxel selected clinical populations also suggests that certain patients may be exquisitely sensitive to targeted therapies that inhibit the HGF/ MET axis.
c-MET also has prognostic implications in patients with cancer.Firstly, overexpression of circulating c- MET in patients with NSCLC has been significantly associated with early tumor recurrence and patients with adenocarcinoma and METamplification have also demonstrated a trend for poor prognosis.Cappuzzo and colleagues have provided clear evidence that increased MET gene copy number is a negative prognostic factor, further supporting anti-c-MET therapeutic strategies in this disease.Of note, data from the same study indicated that epidermal growth factor receptor gene gain has no prognostic function in NSCLC, supporting its role as a predictive factor for improved survival in patients with NSCLC exposed to EGFR tyrosine kinase inhibitors.c-MET is involved in resistance to established agents, such as vascular endothelial growth factor receptor and EGFR inhibitors.For example, the c-MET receptor and VEGFR have been found to cooperate to promote tumor survival.

Furthermore, c-MET has additional roles in tumor angiogenesis; firstly, as an independent angiogenic factor and also one that may interact with angiogenic proliferation and survival signals promoted through VEGF and other angiogenic proteins.Combined VEGF and HGF/c-MET signaling has also been reported to have a greater effect on the prevention of endothelial cell apoptosis, formation of capillaries in vivo, and the increase of microvessel density within tumors.For EGFR, c-MET has been implicated in cooperating as a mediator of EGFR tyrosine Capecitabine phosphorylation and cell growth in the presence of EGFR inhibitors.MET amplification is responsible for EGFR-TKI acquired resistance in approximately 20% of patients.Recent findings from Pillay and colleagues suggest that inhibition of a dominant oncogene by targeted therapy can also alter the hierarchy of receptor tyrosine kinases, resulting in rapid therapeutic resistance.