# ErbB4 Is a Potential Key Regulator of the Pathways Activated by NTRK-Fusions in Thyroid Cancer
## 4 Discussion
This was done with the use of the GeneWays and TRANSPATH databases that gave us, on one side, a very broad scope of interactions (provided by the text-mining based database GeneWays) and, on the other, highly accurate information about the details of signal transduction reactions (provided by the manually curated and highly comprehensive database TRANSPATH). This combination of two databases helped us to achieve the most reliable results of our analysis. The _ERBB4_ gene is a member of the epidermal growth factor receptor family and plays a vital role in normal tissue development, especially in the nervous system [29; 30; 31]. For some tumors, its expression has prognostic value [32], and for some tumors, it is also considered a prospective therapeutic target [33; 34]. The _EGFR_ gene is another member of the EGFR family whose role in tumorigenesis is well known, and many small molecule inhibitors and monoclonal antibodies have been developed to treat non-small-cell lung cancer, pancreatic cancer, breast cancer, and colon cancer [35]. However, EGFR also has a significant kinase-independent pro-survival function, whose mechanism is mainly unknown but may lead to anti-EGFR resistance [36]. Another known example of anti-EGFR resistance is the activation of BDNF/TrkB signaling [37] that links Trk-receptor functionally with EGFR. _BMX_ is a gene encoding a nonreceptor tyrosine kinase [38] for which participation in myocardial hypertrophy [39], inflammation [40], keratinocyte proliferation [41], and castration-resistant prostate cancer development [42] is known. Moreover, a recent study showed that a BMX-ARHGAP fusion protein might activate the JAK/STAT3 signaling pathway [43], which contributes to gastric cancer tumorigenicity. _FLRT3_ is a gene of the FLRT gene family participating in somite development [44]. However, its role in endothelial cell survival, migration, and tube formation after the vascular endothelial growth factor (VEGF) binds to VEGF receptor (VEGF) was recently shown [45]. Furthermore, another gene, _AUTS2_, in addition to its essential role in synapse formation [46; 47], has been shown to be a master regulator of genes for the development of the nervous system [48]. Moreover, for the Drosophila melanogaster homolog of _AUTS2_, Tay Bridge, negative regulation of EGFR-signaling has been shown [49] that may shed light on the link between ERBB4 and AUTS2 identified in our data. Interestingly, we can confirm the possible use of some of the identified master-regulator proteins as diagnostic and prognostic biomarkers by comparison with recently published independent proteomics data of papillary thyroid carcinoma samples [50]. Among more than 2500 proteins identified in that study as specifically detected or overexpressed in the samples of thyroid tumors, two top proteins matched the master regulators identified in our work: Dkk-1 (DKK1), and Cool-1 (ARHGEF7). The protein Dkk-1 (Dickkopf homolog 1) is an LDL receptor ligand that acts in the canonical Wnt signaling pathway. It is upregulated in Alzheimer's disease, nerve degeneration, ankylosing spondylitis, osteoporosis, and lung and several other cancers. It was earlier shown that Dkk-1 overexpression triggers an activation of the Wnt pathway that contributes to resistance to the antitumor drug lbrutinib, targeting ErbB4 [34]. The intriguing role of the Cool-1 (ARHGEF7) protein in cancerogenesis was described earlier [51]. Cool-1 is a Rho guanine nucleotide exchange factor 7 that plays a role in transmembrane receptor protein tyrosine kinase signaling, synaptogenesis, and cytoskeleton organization, regulating cell shape and dendrite development. The whole-genome sequencing of metastatic tumors recently revealed the _ARHGEF7_ gene as playing a central role in metastasis evolution [52]. The identified potential participants and regulators of the pathways activated by the NTRK gene fusion formation may partially explain the resistance mechanism to Trk-inhibitors and propose new targets for overcoming this resistance.