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Open AccessFeature PaperArticle

The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer

1
School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia
2
Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, NSW 2305, Australia
3
School of Mathematical and Physical Sciences, Faculty of Science and Information Technology, University of Newcastle, Callaghan, NSW 2308, Australia
4
School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia
*
Author to whom correspondence should be addressed.
Contributed equally to the study.
Biomolecules 2020, 10(9), 1329; https://doi.org/10.3390/biom10091329
Received: 19 August 2020 / Revised: 13 September 2020 / Accepted: 15 September 2020 / Published: 17 September 2020
(This article belongs to the Special Issue Protein Phosphorylation in Cancer: Unraveling the Signaling Pathways)
The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). TrkA was expressed in cancer epithelial and myoepithelial cells, with higher levels of TrkA positively associated with IDC (39% of cases) (p < 0.0001). Interestingly, TrkA was significantly increased in tumours expressing the human epidermal growth factor receptor-2 (HER2), with expression in 49% of HER2-positive compared to 25% of HER2-negative tumours (p = 0.0027). A panel of breast cancer cells were used to confirm TrkA protein expression, demonstrating higher levels of TrkA (total and phosphorylated) in HER2-positive cell lines. Functional investigations using four different HER2-positive breast cancer cell lines indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability, through decreased phospho-TrkA (Tyr490) and downstream AKT (Ser473) activation, but did not display synergy with Herceptin. Overall, these data highlight a relationship between the tyrosine kinase receptors TrkA and HER2 and suggest the potential of TrkA as a novel or adjunct target for HER2-positive breast tumours. View Full-Text
Keywords: breast cancer; tyrosine kinase receptor A (NTRK1/TrkA); human epidermal growth factor receptor 2 (HER2); clinical biomarker; therapeutic target breast cancer; tyrosine kinase receptor A (NTRK1/TrkA); human epidermal growth factor receptor 2 (HER2); clinical biomarker; therapeutic target
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Griffin, N.; Marsland, M.; Roselli, S.; Oldmeadow, C.; Attia, J.; Walker, M.M.; Hondermarck, H.; Faulkner, S. The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer. Biomolecules 2020, 10, 1329.

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