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: