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Landscape of Epidermal Growth Factor Receptor Heterodimers in Brain Metastases

Lim, Malcolm; Nguyen, Tam H; Niland, Colleen; Reid, Lynne E; Jat, Parmjit S; Saunus, Jodi M; Lakhani, Sunil R; (2022) Landscape of Epidermal Growth Factor Receptor Heterodimers in Brain Metastases. Cancers , 14 (3) , Article 533. 10.3390/cancers14030533. Green open access

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Abstract

HER2+ breast cancer patients have an elevated risk of developing brain metastases (BM), despite adjuvant HER2-targeted therapy. The mechanisms underpinning this reduced intracranial efficacy are unclear. We optimised the in situ proximity ligation assay (PLA) for detection of the high-affinity neuregulin-1 receptor, HER2-HER3 (a key target of pertuzumab), in archival tissue samples and developed a pipeline for high throughput extraction of PLA data from fluorescent microscope image files. Applying this to a large BM sample cohort (n = 159) showed that BM from breast, ovarian, lung and kidney cancers have higher HER2-HER3 levels than other primary tumour types (melanoma, colorectal and prostate cancers). HER2 status, and tumour cell membrane expression of pHER2(Y1221/1222) and pHER3(Y1222) were positively, but not exclusively, associated with HER2-HER3 frequency. In an independent cohort (n = 78), BM had significantly higher HER2-HER3 levels than matching primary tumours (p = 0.0002). For patients who had two craniotomy procedures, HER2-HER3 dimer levels were lower in the consecutive lesion (n = 7; p = 0.006). We also investigated the effects of trastuzumab and pertuzumab on five different heterodimers in vitro: HER2-EGFR, HER2-HER4, HER2-HER3, HER3-HER4, HER3-EGFR. Treatment significantly altered the absolute frequencies of individual complexes in SKBr3 and/or MDA-MB-361 cells, but in the presence of neuregulin-1, the overall distribution was not markedly altered, with HER2-HER3 and HER2-HER4 remaining predominant. Together, these findings suggest that markers of HER2 and HER3 expression are not always indicative of dimerization, and that pertuzumab may be less effective at reducing HER2-HER3 dimerization in the context of excess neuregulin.

Type: Article
Title: Landscape of Epidermal Growth Factor Receptor Heterodimers in Brain Metastases
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.3390/cancers14030533
Publisher version: https://doi.org/10.3390/cancers14030533
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Science & Technology, Life Sciences & Biomedicine, Oncology, brain metastases, HER family, HER dimers, breast cancer, proximity ligation assay, NERVOUS-SYSTEM METASTASES, BREAST-CANCER CELLS, PHOSPHATIDYLINOSITOL 3-KINASE, TRASTUZUMAB, ERBB3, ACTIVATION, EXPRESSION, RESISTANCE, INHIBITOR, TAMOXIFEN
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10150509
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