ADAM-17: a novel therapeutic target for triple negative breast cancer

Abstract

It is concluded that inhibition of ADAM-17, especially in combination with chemotherapy or anti-EGFR/HER inhibitors, may be a new approach for treating breast cancer, including patients with TN disease.

The ADAMs family of proteases as targets for the treatment of cancer

“…In addition to the anti-growth activity found with PF-5480090 alone, pre-incubation with the compound enhanced response to several different cytotoxic drugs (carboplatin and doxorubicin) and anti-HER agents (neratinib and afatinib). 43 A potentially clinically relevant result obtained from the panel of cell lines investigated, was that response to PF-5480090 correlated significantly with cellular levels of ADAM17 catalytic activity. This in vitro finding suggests that if PF-5480090 were to enter clinical trials, a candidate predictive marker might be available for identifying potentially responsive patients.…”

“…42 As with INCB3619, studies in an animal model showed no evidence of fibroplasia following administration of PF-5480090. 42 Using a large panel of breast cancer cell lines in culture, McGowan et al 43 found that PF-5480090 reduced the formation of soluble TGF-a, decreased levels of phosphorylated EGFR and inhibited proliferation in a cell line-dependent manner. Inhibition of cell growth was found to be independent of the molecular subtype of the cell line, i.e., whether cells were estrogen receptor (ER)-positive, HER2-positive or triple-negative.…”

“…This in vitro finding suggests that if PF-5480090 were to enter clinical trials, a candidate predictive marker might be available for identifying potentially responsive patients. 43 Of course, prior to any routine clinical use, the predictive impact of ADAM17 would need to be confirmed in clinical trials.…”

Comparative antiproliferative effects of iniparib and olaparib on a panel of triple-negative and non-triple-negative breast cancer cell lines

“…Cell proliferation was assessed using the MTT Cell Proliferation Kit I (Roche Applied Science) as previously described. 31 To test the effect of iniparib or olaparib on proliferation, cells were plated at a density of 1 × 10 3 per well in 96-well flat-bottomed plates (Corning Costar, Sigma-Aldrich). Following overnight incubation, quadruplicate wells were treated with varying concentrations of compounds alone or in combination, for 5 d.…”

Targeting EGFR in Metastatic Colorectal Cancer Beyond the Limitations of KRAS Status: Alternative Biomarkers and Therapeutic Strategies

“…Aside from its putative role as a predictive biomarker, ADAM-17 could be targeted in combination with EGFR antibodies or other kinase inhibitors, as inhibitors of ADAM-17 have already shown promising results in preclinical models of breast [73] and ovarian [74] cancers, as well as inhibiting EGFR-mediated inflammatory signaling in the chronic autoimmune disorder Sjögren's syndrome [75]. As EGFR ligands are capable of activating paracrine proliferative signaling in neighboring cells, and because ADAM-17 is also involved in shedding of chemokines from immune cells [76], measuring EGFR ligands in combination with the mutation status of the primary tumor could be of prognostic or predictive value.…”