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Targeting ADAM-17 with an inhibitory monoclonal antibody has antitumour effects in triple-negative breast cancer
F Caiazza1, P M McGowan1, M Mullooly1
1UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
Background:
Identification and validation of a targeted therapy for triple-negative breast cancer (TNBC), that is, breast cancers negative for oestrogen receptors, progesterone receptors and HER2 amplification, is currently one of the most urgent problems in breast cancer treatment. EGFR is one of the best-validated driver genes for TNBC. EGFR is normally activated following the release of ligands such as TGFα, mediated by the two MMP-like proteases ADAM (a disintegrin and metalloproteinase)-10 and ADAM-17. The aim of this study was to investigate the antitumour effects of a monoclonal antibody against ADAM-17 on an in vitro model of TNBC.
Methods:
We investigated an inhibitory cross-domain humanised monoclonal antibody targeting both the catalytic domain and the cysteine-rich domain of ADAM17-D1(A12) in the HCC1937 and HCC1143 cell lines.
Results:
D1(A12) was found to significantly inhibit the release of TGFα, and to decrease downstream EGFR-dependent cell signalling. D1(A12) treatment reduced proliferation in two-dimensional clonogenic assays, as well as growth in three-dimensional culture. Furthermore, D1(A12) reduced invasion of HCC1937 cells and decreased migration of HCC1143 cells. Finally, D1(A12) enhanced cell death in HCC1143 cells.
Conclusion:
Our in vitro findings suggest that targeting ADAM-17 with D1(A12) may have anticancer activity in TNBC cells.
Insights
Targeting ADAM-17 with the D1(A12) antibody shows promise for treating triple-negative breast cancer (TNBC). This antibody inhibits tumor cell growth, invasion, and migration, suggesting potential anticancer activity in TNBC models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies, presenting a critical unmet need.
- Epidermal Growth Factor Receptor (EGFR) is a validated driver in TNBC.
- EGFR activation is mediated by TGFα release, facilitated by ADAM-10 and ADAM-17 proteases.
Purpose of the Study:
- To investigate the anti-tumor effects of a monoclonal antibody targeting ADAM-17 in an in vitro TNBC model.
- To evaluate the efficacy of D1(A12), a humanized monoclonal antibody against ADAM-17.
Main Methods:
- Utilized HCC1937 and HCC1143 cell lines for in vitro studies.
- Investigated a monoclonal antibody, D1(A12), targeting both catalytic and cysteine-rich domains of ADAM-17.
- Assessed inhibition of TGFα release, EGFR signaling, cell proliferation, invasion, migration, and cell death.
Main Results:
- D1(A12) significantly inhibited TGFα release and downstream EGFR signaling.
- Treatment with D1(A12) reduced proliferation in 2D and 3D cultures.
- D1(A12) decreased invasion in HCC1937 cells and migration in HCC1143 cells, while enhancing cell death in HCC1143 cells.
Conclusions:
- Targeting ADAM-17 with the D1(A12) antibody demonstrates potential anticancer activity against TNBC cells in vitro.
- These findings support further investigation of D1(A12) as a targeted therapy for TNBC.
