The c-MET oncoprotein: Function, mechanisms of degradation and its targeting by novel anti-cancer agents

• Published in: Biochimica et Biophysica Acta (BBA) - General Subjects Vol. 1864; no. 10; p. 129650
• Main Authors: Park, Kyung Chan, Richardson, Des R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2020; Elsevier BV
• Subjects: Animals; antineoplastic activity; Antineoplastic Agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents, Immunological; Antineoplastic Agents, Immunological - chemistry; Antineoplastic Agents, Immunological - pharmacology; c-MET; Cancer therapeutics; Degradation; Disease Progression; Drug Discovery; gene expression regulation; Humans; iron; lysosomes; messenger RNA; Molecular Targeted Therapy; neoplasm progression; Neoplasms; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; oncogene proteins; proteasome endopeptidase complex; proteinases; Proteolysis; Proteolysis - drug effects; Proto-Oncogene Proteins c-met; Proto-Oncogene Proteins c-met - analysis; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Receptor tyrosine kinase; therapeutics; Thiosemicarbazones; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacology; Degradation; Receptor tyrosine kinase; c-MET; Cancer therapeutics; Thiosemicarbazones
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2020.129650

The c-MET oncoprotein drives cancer progression in a variety of tumors through its signaling transduction pathways. This oncoprotein is also degraded by multiple mechanisms involving the lysosome, proteasome and cleavage by proteases. Targeting c-MET degradation pathways may result in effective therapeutic strategies. Since the discovery of oncogenic functions of c-MET, there has been a great deal of effort to develop anti-cancer drugs targeting this oncoprotein. Unexpectedly, novel di-2-pyridylketone thiosemicarbazones that demonstrate marked anti-tumor activity, down-regulate c-MET through their ability to bind intracellular iron and via mechanisms including, down-regulation of MET mRNA, enhanced lysosomal processing and increased metalloprotease-mediated cleavage. The c-MET oncoprotein regulation and degradation pathways are complex. However, with increasing understanding of its degradation mechanisms, there is also greater opportunities to therapeutically target these pathways. Understanding the mechanisms of degradation of c-MET protein and its regulation could lead to novel therapeutics. [Display omitted] •Diverse c-MET degradation mechanisms lead to therapeutics targeting these pathways.•c-MET targeting agents can be effective in advanced cancers with MET aberration.•Dp44mT and DpC induce c-MET degradation in cancer cells via multiple mechanisms.