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Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

Lazaro, Glorianne, Smith, Chris, Goddard, Lindy, Jordan, Nicola Jane, McClelland, Richard Andrew, Barrett-Lee, Peter, Nicholson, Robert Ian and Hiscox, Stephen Edward 2013. Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response. Endocrine Related Cancer 20 (5) , pp. 691-704. 10.1530/ERC-13-0019

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Abstract

The HER2 transmembrane receptor is a well-characterised predictive marker for trastuzumab benefit and may be associated with decreased benefit from endocrine therapy use. Despite the clinical effectiveness of anti-HER2 agents in such cases, resistance represents a significant limiting factor. Focal adhesion kinase (FAK) plays an important role in HER2 signalling, mediating downstream Akt activation in addition to HER2 cross talk with other growth factor receptors. In this study, we investigated the therapeutic potential of FAK in oestrogen receptor-positive (ERC)/HER2C breast cancer using the novel FAK-specific inhibitor PF4554878 (‘PF878’). The activation of the FAK/HER2 signalling pathway was assessed in ERC/HER2K(MCF7 and T47D) and ERC/HER2C(BT-474 and MDAMB361) breast cancer cells in the presence or absence of PF878 and PF878Gtrastuzumab. The effects of PF878 on cell growth as a monotherapy and in combination with trastuzumab were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Coulter counting with isobologram analysis to determine synergy/additive effects. FAK activation (at Y861 but not at Y397) was highest in ERC/HER2C cells, which also demonstrated the greatest sensitivity to PF878. As a monotherapy, PF878 prevented heregulin-induced MDA361 cell migration, but had no significant effect on cell growth. The treatment of ERC/HER2C cells with PF878 and trastuzumab in combination resulted in the synergistic inhibition of cell proliferation. Underlying this was an abrogation of Akt activity and increased poly(ADP-ribose) polymerase cleavage, effects that were greatest in trastuzumab-refractory MDA361 cells. Collectively, these data support a role for FAK in ERC/HER2C breast cancer, where its targeting has the potential to improve trastuzumab response. This is particularly important in the context of ERC/HER2C, trastuzumab-refractory disease, where FAK inhibition may present an important strategy to restore trastuzumab sensitivity.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: focal adhesion kinase; human epidermal growth factor receptor 2; HER2; luminal B breast cancer; trastuzumab; breast cancer
Publisher: Society of Endocrinology
ISSN: 1479-6821
Funders: Cancer Research Wales, Pfizer Ltd
Last Modified: 13 Jun 2019 03:05
URI: http://orca-mwe.cf.ac.uk/id/eprint/52109

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