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 over-expressed 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 IL-6R; the Notch receptors; type-I and -III TGF-β receptors; receptor tyrosine kinases (RTKs) 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.

CXCR4 Accelerates Osteoclastogenesis Induced by Non-Small Cell Lung Carcinoma Cells Through Self-Potentiation and VCAM1 Secretion

“…Previous studies have shown that ADAM17 is responsible for the shedding of numerous receptors for oncogenic growth factors, cytokines and adhesion molecules, including VCAM1 [18]. Meanwhile, aberrant ADAM17 expression is related to aggressive lung cancer and poor prognosis [19]. Recently, it was reported that Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry the incubation was continued for an additional 2 h. The absorbance value (OD) was measured at 450 nm using a microplate reader (Varioskan Flash, Thermo Scientific, USA).…”

Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study

“…These findings are well in line with previous observations. Noteworthy, the ectodomains of these receptors are released upon cleavage by sheddases like ADAM10 and ADAM17, and conditions of shedding as well as the function of the soluble ectodomains are incompletely understood . The shedded receptors can have antagonistic function or act as signal mediators.…”

Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

“…However, the activity of HER2/HER3 signaling can be further potentiated through ADAM10/17-dependent shedding and activation ErbB ligands (e.g. heregulins)[103, 106, 107, 130–132]. It is also appreciated that HER2 receptor can undergo ectodomain cleavage by ADAM10.…”