Selective Inhibition of ADAM Metalloproteases as a Novel Approach for Modulating ErbB Pathways in Cancer

Abstract

Purpose: ErbB receptor signaling pathways are important regulators of cell fate, and their dysregulation, through (epi)genetic alterations, plays an etiologic role in multiple cancers. ErbB ligands are synthesized as membrane-bound precursors that are cleaved by members of the ADAM family of zinc-dependent metalloproteases. This processing, termed ectodomain shedding, is essential for the functional activation of ErbB ligands. Recent studies suggest that elevated levels of ErbB ligands may circumvent the effectiveness of ErbB-targeted therapeutics. Here, we describe the discovery and preclinical development of potent, selective inhibitors of ErbB ligand shedding. Experimental Design: A series of biochemical and cell-based assays were established to identify selective inhibitors of ErbB ligand shedding. The therapeutic potential of these compounds was assessed in multiple in vivo models of cancer and matrix metalloproteaser elated toxicity. Results: INCB3619 was identified as a representative selective, potent, orally bioavailable small-molecule inhibitor of a subset of ADAM proteases that block shedding of ErbB ligands. Administration of INCB3619 to tumor-bearing mice reduced ErbB ligand shedding in vivo and inhibited ErbB pathway signaling (e.g., phosphorylation of Akt), tumor cell proliferation, and survival. Further, INCB3619 synergized with clinically relevant cancer therapeutics and showed no overt or compounding toxicities, including fibroplasia, the dose-limiting toxicity associated with broad-spectrum matrix metalloprotease inhibitors. Conclusions: Inhibition of ErbB ligand shedding offers a potentially novel and well-tolerated therapeutic strategy for the treatment of human cancers and is currently being evaluated in the clinic.

Role of ADAMs in Cancer Formation and Progression

“…Similarly, little selectivity was found for most of the classical MMPs investigated. Consistent with its ability to inhibit ADAM-10 and ADAM-17 at low levels, INCB3619 blocked the release of TGF-a, HB-EGF, amphiregulin, and heregulin at nanomolar concentrations (53).…”

“…52,53). In contrast, the IC 50 for ADAM-8, ADAM-9, and ADAM-33 were 1,000, >5,000, and 1,036 nM/L, respectively.…”

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

“…Similarly, the combination of valproate, which is known to upregulate cell surface MICA/B (25,55), and metalloproteinase inhibitors substantially stabilized cell surface MICA/B on ovarian carcinoma cells and enhanced the efficacy of immune cell therapy in vivo (56). In addition, the use of ADAM10 and ADAM17 inhibitors was shown to ameliorate the response to chemotherapy treatments in different in vivo models of cancer (57,58), and ADAM inhibitors were used in clinical trials in breast cancer patients (59). Of interest, combined treatment using chemotherapy and metalloproteinase inhibitors recently was proposed as a therapeutic regimen in MM, because drug-induced ADAM-mediated CD138 release was shown to promote tumor growth (60).…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…Indeed, in a mammary cancer model induced by the expression of polyoma middle T oncoprotein, ADAM-12 has been shown to increase stromal cell apoptosis and decrease tumour cell apoptosis [91]. INCB3619, a selective inhibitor of a subset of ADAM proteinases, blocks the shedding of ErbB ligands, reduces ErbB ligand shedding in vivo and inhibits ErbB pathway signalling, tumour cell proliferation and survival [92]. Altogether, these data emphasize the key role of ADAM proteinases in the regulation of cell proliferation and apoptosis although the dissection of precise mechanisms will necessitate further investigations.…”