ErbB4 Is a Potential Key Regulator of the Pathways Activated by NTRK-Fusions in Thyroid Cancer

Andrey Kechin,Maxim Filipenko,Alexander Kel,Anatoliy Ivanov,Viktoriya Borobova

doi:10.3390/app12052506

Abstract

NTRK gene fusions are drivers of tumorigenesis events that specific Trk-inhibitors can target. Current knowledge of the downstream pathways activated has been previously limited to the pathways of regulator proteins phosphorylated directly by Trk receptors. Here, we aimed to detect genes whose expression is increased in response to the activation of these pathways. We identified and analyzed differentially expressed genes in thyroid cancer samples with NTRK1 or NTRK3 gene fusions, and without any NTRK fusions, versus normal thyroid gland tissues, using data from the Cancer Genome Atlas, the DESeq2 tool, and the Genome Enhancer and geneXplain platforms. Searching for the genes activated only in samples with an NTRK fusion as opposed to those without NTRK fusions, we identified 29 genes involved in nervous system development, including AUTS2, DTNA, ERBB4, FLRT2, FLRT3, RPH3A, and SCN4A. We found that genes regulating the expression of the upregulated genes (i.e., upstream regulators) were enriched in the “signaling by ERBB4” pathway. ERBB4 was also one of three genes encoding master regulators whose expression was increased only in samples with an NTRK fusion. Moreover, the algorithm searching for positive feedback loops for gene promoters and transcription factors (a so-called “walking pathways” algorithm) identified the ErbB4 protein as the key master regulator. ERBB4 upregulation (p-value = 0.004) was confirmed in an independent sample of ETV6-NTRK3-positive FFPE specimens. Thus, ErbB4 is the potential key regulator of the pathways activated by NTRK gene fusions in thyroid cancer. These results are preliminary and require additional biochemical validation.

Highlights

Human NTRK genes (NTRK1, NTRK2, and NTRK3) encode three neurotrophic receptors TrkA, TrkB, and TrkC, respectively
Using the Cancer Genome Atlas (TCGA) data, we investigated genes which were differentially expressed in thyroid tumors containing and not containing NTRK-fusions versus normal thyroid gland data that was recently obtained by Suntsova et al [13]
In the current study, analyzing TCGA gene expression data, we suggested genes that may participate in the tumorigenesis induced by NTRK gene fusions: ERBB4, EGFR, BMX, BMPR1B, AUTS2, DTNA, ERBB4, FLRT2, FLRT3, RPH3A, DKK1, NOG, ARHGEF7, and

Summary

Introduction

Human NTRK genes (NTRK1, NTRK2, and NTRK3) encode three neurotrophic receptors TrkA, TrkB, and TrkC, respectively. E.g., thyroid glands, their role is unclear, but their aberrant activation, which happens mainly through gene fusion with other constitutively expressed genes, may lead to the activation of the mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K)/AKT, phospholipase C gamma (PLCγ)-Ca2+ , nuclear factor-kappa B (NF-κB), and protein kinase C (PKC) pathways, and tumorigenesis [1]. Tumors developed via this mechanism are sensitive to NTRK-inhibitors, e.g., larotrectenib or entrectinib, which have a high response rate with low toxicity [3]. Due to the low occurrence of NTRK-fusions (~0.3% in all solid tumors) [4], and relatively recent development of effective methods for NTRK rearrangement detection [5,6], previous studies were mainly focused on the biochemical analysis of activated Trk partner proteins, or the properties of the fused proteins themselves

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