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

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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 STAT3Y705 is upregulated and phosphorylated p21T145 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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Funding

The work was supported by the College of Pharmacy and Nutrition, University of Saskatchewan, Canada and an NSERC grant to MKS (417652).

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Authors and Affiliations

  1. College of Pharmacy and Nutrition, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada

    Chandra Bose Prabaharan, Divya Chidambaram, Karthic Rajamanickam & Meena Kishore Sakharkar

  2. Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada

    Allan Boyao Yang

  3. Vaccine and Infectious Disease Organization-International Vaccine Research Centre, University of Saskatchewan, 120 Veterinary Road, Saskatoon, SK, S7N 5E3, Canada

    Scott Napper

  4. Department of Biochemistry, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada

    Scott Napper

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  1. Chandra Bose Prabaharan
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Electronic supplementary material

Supplementary Figure S1a

The frequency and distribution of DEPs in different cellular pathways based on gene ontology analyses: (A) biochemical processes, (B) molecular function, and (C) subcellular compartments in BT474 after Ibrutinib treatment. (PPTX 2897 kb)

Supplementary Figure S1b

The frequency and distribution of DEPs in different cellular pathways based on gene ontology analyses: (A) biochemical processes, (B) molecular function, and (C) subcellular compartments in SKBR3 after Ibrutinib treatment. (PPTX 2774 kb)

Supplementary Figure S2a

The frequency and distribution of DEPs in different pathways based on InnateDB in BT474. (PPTX 1120 kb)

Supplementary Figure S2b

The frequency and distribution of DEPs in different pathways based on InnateDB in SKBR3. (PPTX 1101 kb)

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Prabaharan, C.B., Yang, A.B., Chidambaram, D. et al. Ibrutinib as a potential therapeutic option for HER2 overexpressing breast cancer – the role of STAT3 and p21. Invest New Drugs 38, 909–921 (2020). https://doi.org/10.1007/s10637-019-00837-w

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