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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
MET [also known as, hepatocyte growth factor receptor (HGFR)] is a transmembrane receptor protein tyrosine kinase. Hepatocyte growth factor (HGF), secreted by fibroblasts and smooth muscle cells, binds to the MET receptor and induces MET dimerization and autophosphorylation, leading to the activation of tyrosine kinase [48]. MET mediates activation of downstream signaling pathways, including phosphoinositide 3-kinase (PI3K)/AKT, Ras-Rac/Rho, mitogen-activated protein kinase, and phospholipase C, that stimulate pathways involved in cell growth, apoptosis, motility, and invasiveness [49]. MET pathway is dysregulated in multiple human cancers, including lung adenocarcinoma [48]. Several mechanisms of MET pathway overexpression have been identified, namely, receptor overexpression, constitutive kinase activation, gene amplification, paracrine/autocrine activation via HGF, MET mutation or epigenetic mechanisms (tumor secreted growth factors, hypoxia, and other oncogenes) [48, 50].
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Crizotinib competes with ATP for the ALK kinase domain of the EML4-ALK fusion protein which was first described in a Nature publication in 2007. Approximately 5% of patients with NSCLC carry the fusion protein, and patients with this mutation are typically non-smokers who do not have mutations in their EGFR or K-RAS genes. ALK mutations are also thought to be important in driving the malignant phenotype in a significant percentage (~15%) of cases of neuroblastoma, a rare form of nervous system cancer that occurs almost exclusively in young children. There is also some evidence that crizotinib inhibits the c-Met/Hepatocyte Growth Factor Receptor (HGFR) tyrosine kinase which is thought to be involved in several other tumor types.
Normal and Abnormal Development of the Biliary Tree
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Most recendv, a gene on 6p21.1-p12 has been identified for autosomal recessive polycystic kidney disease.88,89 This large and complex gene extends over 469 kb, and in a minimum of 86 exons encodes a member of a novel class of proteins that share structural features with hepatocyte growth factor receptor and plexins. These in turn belong to a superfamily of proteins involved in regulation of cell proliferation and of cellular adhesion and repulsion; a class of proteins of considerable interest for organogenesis.
Synthesis and biological evaluation of novel (E)-N'-benzylidene hydrazides as novel c-Met inhibitors through fragment based virtual screening
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Jing-wei Liang, Shi-long Li, Shan Wang, Wan-qiu Li, Fan-hao Meng
Hepatocyte growth factor receptor (HGFR/c-Met) is a transmembrane heterodimer comprising two disulphide-linked chains, including an outer α-chain (50 kDa) and a transmembrane β-chain (140 kDa)1, encoded by c-Met gene2. Under normal physiological conditions, it regulates important cellular processes, such as differentiation, proliferation, cell cycle, motility, and apoptosis. The intracellular portion of c-Met comprises a catalytic tyrosine kinase domain, which contains multifunctional docking sites3. Many downstream pathways such as PI3K, MAPK, and STAT3 will be activated, when the HGF binds to the extracellular domains of c-Met, followed by autophosphorylation of tyrosine kinase residues in the catalytic domain4. Abnormal activation in the c-Met pathway induces excessive cell proliferation and is related to the development and progression of the neoplastic disease5.
Genomics in non-adenoid cystic group of salivary gland cancers: one or more druggable entities?
Published in Expert Opinion on Investigational Drugs, 2019
Stefano Cavalieri, Francesca Platini, Cristiana Bergamini, Carlo Resteghini, Donata Galbiati, Paolo Bossi, Federica Perrone, Elena Tamborini, Pasquale Quattrone, Lisa Licitra, Laura Deborah Locati, Salvatore Alfieri
MET gene codifies for the hepatocyte growth factor receptor (HGFR). The activation of this pathway is involved in some type of cancers, notably non-small cell lung cancer (NSCLC) [65,66], and in Hepatocellular carcinoma (HCC) [67]. In a German cohort of 198 non-ACC patients (233 in total, 35 ACC), MET was deleted in only 9% of cases [68]. In the majority of non-ACC (57%), a physiological MET disomy was found. Approximately one third of cases had either a polysomy or an amplification of MET gene. The only two cases bearing MET amplification were one adenocarcinoma NOS and one myoepithelial carcinoma. The activity of several MET inhibitors (e.g. crizotinib, capmatinib, cabozantinib) has been explored in NSCLC. However, due to rarity of MET amplification in salivary gland cancers and its general difficulty to be targeted, this test should be performed only in case of lack of all druggable alterations.
c-Met kinase inhibitors: an update patent review (2014-2017)
Published in Expert Opinion on Therapeutic Patents, 2019
Qing-Wen Zhang, Zi-Dan Ye, Lei Shi
c-Met, also termed as hepatocyte growth factor receptor (HGFR), is a member of receptor tyrosine kinase encoded by proto-oncogene Met. It is the only known receptor with high affinity for its naturally occurring ligand hepatocyte growth factor (HGF), also known as scatter factor [1]. The c-Met proto-oncogene is located on human chromosome 7 band 7q21–q31 and encodes a protein, which is approximately 145 kDa in size [2]. The receptor tyrosine kinase c-Met is produced as a single-chain precursor and then processed to form a disulfide-linked glycoprotein heterodimer linked by the extracellular α-subunit and the transmembrane β-subunit [3]. The extracellular part contains region of homology to semaphorins (SEMA), followed by a plexinsemaphorin integrin domain and four immunoglobulin-like domains (Figure 1) [4]. The intracellular segment comprises a juxtamembrane domain, the tyrosine kinase domain besides a C-terminal multifunctional docking site. HGF binding to the extracellular sites results in c-Met dimerization and autophosphorylation of two tyrosine residues Y1234 and Y1235 at the c-Met receptor [5]. Phosphorylation on tyrosine residues Y1349 and Y1356 following receptor activation near the carboxyl terminus produces a docking site for recruitments of intracellular downstream adaptors and effectors to transmit signals [6].