The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer
Autor: | Hubert Hondermarck, Marjorie M. Walker, John Attia, Séverine Roselli, Nathan Griffin, Mark Marsland, Christopher Oldmeadow, Sam Faulkner |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Receptor ErbB-2 lcsh:QR1-502 Tropomyosin receptor kinase A clinical biomarker Biochemistry Receptor tyrosine kinase Tyrosine-kinase inhibitor lcsh:Microbiology Metastasis 0302 clinical medicine human epidermal growth factor receptor 2 (HER2) tyrosine kinase receptor A (NTRK1/TrkA) Medicine Molecular Targeted Therapy skin and connective tissue diseases biology Carcinoma Ductal Breast therapeutic target Middle Aged Immunohistochemistry Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis Female animal structures medicine.drug_class Cell Survival Breast Neoplasms Article 03 medical and health sciences Breast cancer breast cancer Cell Line Tumor Biomarkers Tumor Humans Receptor trkA Molecular Biology Protein kinase B Protein Kinase Inhibitors neoplasms business.industry Cancer medicine.disease Survival Analysis body regions Carcinoma Lobular 030104 developmental biology Carcinoma Intraductal Noninfiltrating nervous system Trk receptor biology.protein Cancer research business |
Zdroj: | Biomolecules, Vol 10, Iss 1329, p 1329 (2020) Biomolecules Volume 10 Issue 9 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |