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Review
. 2017 Feb 1;23(3):623-629.
doi: 10.1158/1078-0432.CCR-16-0869. Epub 2016 Nov 28.

Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer

Miles A Miller  1 , Ryan J Sullivan  2 , Douglas A Lauffenburger  3
Affiliations
Review

Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer

Miles A Miller et al. Clin Cancer Res. .

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.

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Figures

Figure 1
Figure 1. Modes of receptor ectodomain shedding
Left) As an example of activation, ADAM-mediated proteolysis of the Notch receptor is followed by regulated intramembrane proteolysis to enable nuclear translocation and activity. Center) As an example of receptor downregulation, the proteolytic cleavage of MET, AXL, and MerTK decreases surface levels while simultaneously producing soluble decoy receptors that sequester cognate ligands HGF and Gas6. Right) By directly inhibiting sheddases or by targeting the signaling pathways that regulate their activity, previously cleaved receptors accumulate on the cell surface where they signal through compensatory pathways. Decreased levels of soluble decoy receptors allow cognate ligands to activate surface receptors.
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