ADAM10 blocking peptide

Background and AimThe multi-kinase inhibitor regorafenib (REG) was recently demonstrated to be effective in patients with sorafenib (SOR)-resistant hepatocellular carcinoma (HCC). Interestingly, SOR is known to enhance the accumulation of membrane-bound MHC class I polypeptide-related sequence A (mMICA) in HCC cells and to block the production of soluble MICA (sMICA), an immunological decoy. In addition, MICA is associated with HCC in patients with chronic hepatitis C. We have now compared the impact of REG and SOR on MICA in HCC cells, as well as the immunotherapeutic implications thereof. MethodsHepG2 and PLC/PRF/5 cells were exposed to REG and SOR, and levels of sMICA and mMICA were measured by ELISA and flow cytometry, respectively. The drugs were also tested in vitro for inhibitory activity against recombinant human A disintegrin and metalloprotease 9 (ADAM9), a sheddase that releases MICA from the membrane. ResultsTo a greater extent than SOR, but without marked difference in cytotoxicity, REG significantly suppressed mRNA and protein expression of ADAM9 and ADAM10, thereby decreasing production of sMICA and boosting accumulation of mMICA. Accumulation of mMICA in response to REG was reversed by siRNA against ADAM9. However, the drugs did not inhibit the enzymatic activity of ADAM9 in vitro. ConclusionsThe clinical superiority of REG over SOR is partially attributable to reduced MICA shedding via transcriptional suppression of ADAM9 and ADAM10.

Human epidermal growth factor receptor-2 (HER-2) overexpression in breast tumor tissues is associated with a poor prognosis but may benefit from treatment with trastuzumab. The extracellular domain (ECD) of HER-2 can be measured in serum and which has been a new inspection item in clinical laboratory of several hospitals. However, whether serum HER-2 ECD can be a marker of HER-2 status in tumor tissues still confused clinicians. This study is a retrospective observation to explore the correlation between serum HER-2 ECD shedding and tissue HER-2 status in breast cancer patients. Meanwhile, we will further uncover the potential clinical significance of serum HER-2 ECD detection. A total of 545 unselected breast cancer patients from Fudan University Shanghai Cancer Center were enrolled in this study. At primary diagnosis without any treatment, serum HER-2 ECD was measured on ADVIA Centaur assay; meanwhile, tissue HER-2 from core needle biopsy was tested through immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). We showed that serum HER-2 ECD concentration was related to tissue HER-2 status. Nevertheless, 36.9% of patients with tissue HER-2 overexpression had low levels of HER-2 ECD shedding (<15 ng/mL) in serum. Here, we demonstrated that HER-2 ECD shedding was also associated with protein expression and alpha-secretase activity of a disintegrin and metalloproteinase 10 (ADAM10) using tumor tissues and cell lines. Progression-free survival (PFS) data from breast cancer patients in TNM phase II and III with tissue HER-2 IHC 3+ were analyzed using Kaplan-Meier plotter. The patients with serum HER-2 ECD above 15 ng/mL had lower progression-free survival than those with serum HER-2 ECD <15 ng/mL. Thus, serum HER-2 ECD could be a biomarker to identify the subgroup of poorer outcome among HER-2 overexpression breast cancer patients. Inhibition of ADAM10 activity may have potential therapeutic benefit for this most aggressive tumor subgroup.