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02.08.2019 | PRECLINICAL STUDIES

Ibrutinib as a potential therapeutic option for HER2 overexpressing breast cancer – the role of STAT3 and p21

verfasst von: Chandra Bose Prabaharan, Allan Boyao Yang, Divya Chidambaram, Karthic Rajamanickam, Scott Napper, Meena Kishore Sakharkar

Erschienen in: Investigational New Drugs | Ausgabe 4/2020

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Summary

Treatment response rates to current anticancer therapies for HER2 overexpressing breast cancer are limited and are associated with severe adverse drug reactions. Tyrosine kinases perform crucial roles in cellular processes by mediating cell signalling cascades. Ibrutinib is a recently approved Tyrosine Kinase Inhibitor (TKI) that has been shown be an effective therapeutic option for HER2 overexpressing breast cancer. The molecular mechanisms, pathways, or genes that are modulated by ibrutinib and the mechanism of action of ibrutinib in HER2 overexpressing breast cancer remain obscure. In this study, we have performed a kinome array analysis of ibrutinib treatment in two HER2 overexpressing breast cancer cell lines. Our analysis shows that ibrutinib induces changes in nuclear morphology and causes apoptosis via caspase-dependent extrinsic apoptosis pathway with the activation of caspases-8, caspase-3, and cleavage of PARP1. We further show that phosphorylated STAT3^Y705 is upregulated and phosphorylated p21^T145 is downregulated upon ibrutinib treatment. We propose that STAT3 upregulation is a passive response as a result of induction of DNA damage and downregulation of phosphorylated p21 is promoting cell cycle arrest and apoptosis in the two HER2 overexpressing cell lines. These results suggest that inhibitors of STAT3 phosphorylation may be potential options for combination therapy to help increase the efficacy of ibrutinib against HER2-overexpressing tumors.

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Titel: Ibrutinib as a potential therapeutic option for HER2 overexpressing breast cancer – the role of STAT3 and p21
verfasst von: Chandra Bose Prabaharan
Allan Boyao Yang
Divya Chidambaram
Karthic Rajamanickam
Scott Napper
Meena Kishore Sakharkar
Publikationsdatum: 02.08.2019
Verlag: Springer US
Erschienen in: Investigational New Drugs / Ausgabe 4/2020
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-019-00837-w

Springer Medizin

Ibrutinib as a potential therapeutic option for HER2 overexpressing breast cancer – the role of STAT3 and p21

Summary

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Springer Medizin

Summary

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