Differential Effects of Inhibitory and Stimulatory Anti-HER2 Monoclonal Antibodies on AKT/ERK Signaling Pathways

Document Type: Research Articles

Authors

1 Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

2 Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.

Abstract

Objective: Homo- and heterodimerization of the receptor tyrosine kinase HER2 hyperactivate several downstream
signaling pathways, leading to uncontrolled growth and proliferation of tumor cells. Anti-HER2 monoclonal antibodies
(mAbs) may induce different effects on HER2 dimerization and signaling. Methods: The effect of two inhibitory
(2A8, 1T0) and one stimulatory (1H9) anti-HER2 mAbs either alone or in combination with trastuzumab was investigated
on AKT and ERK signaling pathways and HER2 degradation in a human breast cancer cell line (BT-474) by Western
blotting. Result: While 1H9 mAb had no significant effect on AKT and ERK signaling pathways, 1T0 and 2A8 mAbs
inhibited phosphorylation of both pathways. Combination of 1T0 mAb with trastuzumab resulted in significant synergistic
inhibition of both pathways and HER2 degradation, much more potently than the combination of trastuzumab and
pertuzumab. Conclusion: Our data indicate that anti-HER2 mAbs may induce different signaling pathways depending
on their effect on tumor cell growth and proliferation. The significant inhibition of ERK and AKT phosphorylation by
1T0 alone or particularly in combination with trastuzumab suggests its potential therapeutic application for targeted
immunotherapy of HER2 overexpressing malignancies.

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