title: Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer.
abstract: Proteases known as sheddases cleave the extracellular domains of their substrates from the cell surface. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently overexpressed in cancer, and promiscuously cleaving diverse substrates. It is increasingly clear that the proteolytic shedding of transmembrane receptors impacts pathophysiology and drug response. Receptor substrates of sheddases include the cytokine receptors TNFR1 and IL6R; the Notch receptors; type-I and -III TGFβ receptors; receptor tyrosine kinases (RTK) such as HER2, HER4, and VEGFR2; and, in particular, MET and TAM-family RTKs AXL and Mer (MerTK). Activation of receptor shedding by mechanical cues, hypoxia, radiation, and phosphosignaling offers insight into mechanisms of drug resistance. This particularly holds for kinase inhibitors targeting BRAF (such as vemurafenib and dabrafenib) and MEK (such as trametinib and cobimetinib), along with direct sheddase inhibitors. Receptor proteolysis can be detected in patient fluids and is especially relevant in melanoma, glioblastoma, lung cancer, and triple-negative breast cancer where RTK substrates, MAPK signaling, and ADAMs are frequently dysregulated. Translatable strategies to exploit receptor shedding include combination kinase inhibitor regimens, recombinant decoy receptors based on endogenous counterparts, and, potentially, immunotherapy. Clin Cancer Res; 23(3); 623-9. ©2016 AACR.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Miles A
authors.initials: MA
authors.lastname: Miller
authors.affiliation: Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Sullivan
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts. lauffen@mit.edu.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
mesh_terms: D000072197:ADAM10 Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D000072198:ADAM17 Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D001826:Body Fluids / Q000737:chemistry; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D007167:Immunotherapy; D008264:Macrophages / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D059748:Proteolysis / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013379:Substrate Specificity; D019714:Tissue Inhibitor of Metalloproteinases / Q000502:physiology; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D011956:Receptors, Cell Surface; D019714:Tissue Inhibitor of Metalloproteinases; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein