Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer
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 cl...
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| Format: | Article |
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American Association for Cancer Research (AACR)
2018
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| Online Access: | http://hdl.handle.net/1721.1/117690 https://orcid.org/0000-0002-0050-989X |
| _version_ | 1826206180406460416 |
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| author | Miller, Miles A. Sullivan, Ryan J. Lauffenburger, Douglas A |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Miller, Miles A. Sullivan, Ryan J. Lauffenburger, Douglas A |
| author_sort | Miller, Miles A. |
| collection | MIT |
| description | 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 triplenegative 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. |
| first_indexed | 2024-09-23T13:25:22Z |
| format | Article |
| id | mit-1721.1/117690 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:25:22Z |
| publishDate | 2018 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1176902022-09-28T14:06:03Z Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer Miller, Miles A. Sullivan, Ryan J. Lauffenburger, Douglas A Massachusetts Institute of Technology. Department of Biological Engineering Lauffenburger, Douglas A 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 triplenegative 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. National Cancer Institute (U.S.) (Grant K99-CA207744) National Cancer Institute (U.S.) (Grant R01-CA96504) National Cancer Institute (U.S.) (Grant U54-CA112967) 2018-09-10T18:54:35Z 2018-09-10T18:54:35Z 2016-11 2016-11 2018-09-10T13:30:30Z Article http://purl.org/eprint/type/JournalArticle 1078-0432 1557-3265 http://hdl.handle.net/1721.1/117690 Miller, Miles A. et al. “Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer.” Clinical Cancer Research 23, 3 (November 2016): 623–629 © 2016 AACR https://orcid.org/0000-0002-0050-989X http://dx.doi.org/10.1158/1078-0432.CCR-16-0869 Clinical Cancer Research Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | Miller, Miles A. Sullivan, Ryan J. Lauffenburger, Douglas A Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer |
| title | Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer |
| title_full | Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer |
| title_fullStr | Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer |
| title_full_unstemmed | Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer |
| title_short | Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer |
| title_sort | molecular pathways receptor ectodomain shedding in treatment resistance and monitoring of cancer |
| url | http://hdl.handle.net/1721.1/117690 https://orcid.org/0000-0002-0050-989X |
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