Abstract
Breast cancer is the most common female cancerous disease and the second most cause of cancer death in women. About 20–30% of these tumors exhibit an amplification of the HER2/ErbB2 receptor, which is coupled to a more aggressive and invasive growth of the cancer cells. Recently developed tyrosine kinase inhibitors and therapeutic antibodies targeting the HER2 receptor improved the overall survival time compared with sole radio- and chemotherapy. Upcoming resistances against the HER2-targeted therapy make a better understanding of the receptor associated downstream pathways an absolute need. In earlier studies, we showed the involvement of Protein Tyrosine Phosphatase Interacting Protein 51 (PTPIP51) in the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is one of the most frequently overactivated pathways in HER2-amplified breast cancer cells. This study is aimed to elucidate the effects of four different TKIs on the interactome of PTPIP51, namely with the receptors EGFR and HER2, 14-3-3/Raf1 (MAPK pathway), its regulating enzymes, and the mitochondria-associated interaction partners in HER2 breast cancer cell lines (SK-BR3 and BT474) by using the Duolink proximity ligation assay, immunoblotting and knockdown of PTPIP51. Inhibition of both EGFR and HER2/ErbB2R shifted PTPIP51 into the MAPK pathway, but left the mitochondria-associated interactome of PTPIP51 unattended. Exclusively inhibiting HER2/ErbB2 by Mubritinib did not affect the interaction of PTPIP51 with the MAPK signaling. Selective inhibition of HER2 induced great alterations of mitochondria-associated interactions of PTPIP51, which ultimately led to the most-effective reduction of cell viability of SK-BR3 cells of all tested TKIs. The results clearly reveal the importance of knowing the exact mechanisms of the inhibitors affecting receptor tyrosine kinases in order to develop more efficient anti-HER2-targeted therapies.
Highlights
The identification of targetable signal nodes and protein–protein interactions is of utmost interest for the development of novel drugs for the treatment of cancer and other diseases such as neurodegenerative diseases
Selective inhibition of human epidermal growth factor receptor (EGFR)-related receptor 2 (HER2) strongly affects the mitochondrial metabolism in SK-BR3 cells To monitor the effects of selective and simultaneous inhibition of EGFR and HER2 on mitochondrial metabolism, 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl2H-tetrazolium bromide (MTT) assays were performed
EGFR and HER3, the receptor signaling of HER2 is coupled for example to the mitogen-activated protein kinase (MAPK) pathway, to PI3K and Akt signaling[1]
Summary
The identification of targetable signal nodes and protein–protein interactions is of utmost interest for the development of novel drugs for the treatment of cancer and other diseases such as neurodegenerative diseases. The already clinically established tyrosine kinase inhibitor Lapatinib, which targets epidermal growth factor receptor (EGFR) and HER2, improved the time to progression from 4.4 months to 8.4 months in a capecetabin vs capecetabine plus lapatinib setting[4]. HER2, known as ErbB2 (erythroblastosis homolog B2), is an orphan receptor. It belongs to the Her family like the EGFR. As there is no identified ligand of the HER2 receptor, the downstream signaling is activated by autophosphorylation through the formation of homodimers or heterodimers with other members of the Her family. HER2 signaling is channeled into the MAPK and PI3K/Akt signaling leading to proliferation, growth, and survival of the cell
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