Abstract
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.
Highlights
Targeted therapies against the human epidermal growth factor receptor-2 (HER2) have demonstrated their clinical efficacy in breast cancer
The results (Figure 1) indicated that NTRK1 gene expression was altered in 6% (52 cases) of breast tumours with 31 amplifications, 3 missense mutations, 13 mRNA upregulations and 5 mRNA downregulations (Figure 1A)
Prior to immunohistochemical profiling and functional investigations, data mining of TrkA (NTRK1) gene expression was performed using the cBioPortal cancer genomics platform of the PAM50 dataset from The Cancer Genome Atlas (TCGA) database, which demonstrated that alterations are observed in a moderate proportion of breast tumours
Summary
Targeted therapies against the human epidermal growth factor receptor-2 (HER2) have demonstrated their clinical efficacy in breast cancer. There are no clinically validated predictive biomarkers and the use of anti-HER2 agents is still determined based on the HER2 status of the primary tumour. A key oversight in current diagnostic and prognostic methodologies is that HER2 status of the primary tumour may vary compared to metastases in approximately 25% of all cases [4,5]. This further highlights the crucial need to identify biomarkers of resistance and metastatic progression as well as adjunct therapeutic targets for improving the management of HER2-positive breast cancer [2,6]
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