FusionPlex NTRK Kit

Neurotrophic tyrosine kinase gene fusions are found in a broad range of cancers such as adenocarcinomas, high-grade gliomas, pilocytic astrocytomas and leukemias. Their pan-cancer involvement, coupled to potential treatment with tyrosine kinase inhibitors, makes research and identification of NTRK fusions crucial.

The Archer® FusionPlex® NTRK Kit is a targeted sequencing assay that detects and identifies fusions to NTRK1, NTRK2 and NTRK3, even without prior knowledge of fusion partners or breakpoints. FusionPlex kits combine a simple lyophilized workflow, Anchored Multiplex PCR (AMP™) fusion detection technology and comprehensive analysis pipeline to provide comprehensive fusion identification. Libraries are created by using the FusionPlex kit in conjunction with Archer MBC Adapters for Illumina® or Ion Torrent™. Once sequenced, Archer FusionPlex libraries can be analyzed by Archer Analysis to detect and identify fusion partners of NTRK genes reported to be associated with various cancers.


  • Comprehensive panel of NTRK fusion targets
  • Streamlined testing reduces turnaround time – test for all NTRK panel fusions in a single sample.
  • High level reporting supported by detailed analysis – no programming required
  • Works with FFPE samples

Assay Targets

Table 1: Archer FusionPlex NTRK Kit recognized exons
Target Accession # Exon Direction
NTRK1 NM_002529 8, 10-13 5'
NTRK2 NM_006180 11-17 5'
NTRK3 NM_002530 13-16 5'
NTRK3 NM_001007156 15 5'

NTRK Gene Fusion Map


This diagram shows known NTRK gene fusions documented in the literature. All translocations shown in this figure are detected by this assay.

The NTRK Family

Neurotrophic tyrosine kinases (NTRKs), including NTRK1, NTRK2 and NTRK3, are transmembrane tyrosine kinase receptors involved in central and peripheral nervous system development. The canonical NTRK family-member, NTRK1, shares 47% nucleic acid identity with NTRK2 and NTRK3. Originally characterized as oncogenic fusions with tropomyosin in colon cancer (1, 2) and thyroid carcinomas (3-5), NTRKs were later discovered to be the receptors for nerve growth factors (NGFs) (6). Neurotrophin-binding by NTRKs stimulates homodimerization, autophosphorylation, and subsequent signaling through the PI3K, AKT, and MAPK pathways. Generally, this promotes neuronal cell survival and neuronal subtype differentiation. NTRK activity sustains synaptic activity and neuron growth throughout adulthood (7).

Increasing amounts of tumor sequencing studies highlight the broad cancer-types associated with NTRK gene fusions (shown per gene, below). Many oncogenic NTRK translocations and mutations result in constitutive activation of tyrosine kinase domains, of particular note to researchers given the recent identification of selective tyrosine kinase inhibitors (8-10). Targeted tools, such as the Archer FusionPlex NTRK Panel, can assist researchers in identification and molecular characterization of novel and known fusions of NTRK genes with significantly lower cost than whole-genome or RNA-seq based approaches.

Table 2: Quick facts on NTRK genes
Chromosomal location 1q23.1 9q21.33 15q25
  • Nerve Growth Factor (NGF) (6)
  • Neurotrophin-3 (NTF3, NT-3) (11)
  • Brain-derived neurotrophic factor (BDNF)
  • Neurotrophin-4 (NT4)
  • Neurotrophin-3 (NTF3, NT-3)
  • Neurotrophin-3 (NTF3, NT-3)
Tissue localization
  • TrkA-I: non-neuronal tissues
  • TrkaA-II: neuronal cells
  • TrkA-III: Pluripotent neural stem and neural crest progenitors
  • Central and peripheral nervous system cells
  • Brain (hippocampus, cerebral cortex, granular cell layer of cerebellum


The NTRK1 gene, located on human chromosome 1q23.1, encodes the neurotrophic tyrosine kinase receptor-1, TrkA. TrkA was discovered and characterized as a theretofore unknown tyrosine kinase fused to tropomyosin (TPM3) in colon carcinoma(1, 20) and mutated in thyroid carcinomas(3-5). Subsequent studies revealed TrkA as the high-affinity receptor for nerve growth factor (6), though TrkA also binds neurotrophin-3 (NT3) with lower affinity (11). The binding of NGF or NT3 enables TrkA dimerization and autophosphorylation at multiple tyrosine residues. These phosphorylations facilitate binding of SHC, PLC?, and protein adapters containing PTB domains resulting in activation of the Ras/MAPK, PI3K, Akt and PLC? pathways(7, 21-23).

Three isoforms of NTRK1 are characterized in the literature, TrkA-I found in non-neuronal tissues, TrkA-II in neuronal cell types (24) and TrkA-III in undifferentiated early neural progenitors and neural crest progenitor cells (25). TrkA-III excludes NTRK1 exons 6, 7 and 9 producing a gene product missing several extracellular domains (25). The TrkA-II isoform also excludes the extracellular IG-C1 and N-glycosylation domains, is unresponsive to NGF, and may constitutively activate the IP3K, Akt1 and NFkB pathways (25).

NTRK1 gene fusions are characterized in numerous cancer types. These cancers include intrahepatic cholangiocarcinoma by RABGAP1L-NTRK1 fusion (12), pediatric high-grade glioma with TP53-NTRK1 fusion (14), glioblastoma multiforme brain tumors from BCAN-NTRK1 and NFASC-NTRK1 fusions (15), LMNA-NTRK1 translocation in Spitz tumors and spitzoid melanomas (17), various lung cancers from MPRIP-NTRK1 and CD74-NTRK1 fusions (16), colon carcinoma with TPM3-NTRK1 (1) and papillary thyroid carcinoma (4). The pan-cancer nature of NTRK1 translocations supports the idea that miscreant tyrosine kinase function contributes to transformative phenotypes. This cancer-causing potential may arise through upregulation of the aberrant tyrosine kinase domains (15) or through stimulating dimerization via novel translocated extracellular domains non-responsive to NGF stimulation(16, 17).


NTRK2 (also known as TrkB) is the high-affinity receptor for brain-derived neurotrophic factor, though NTRK2 also binds neurotrophin-4 (NT4)(26-30) and neurotrophin-3 (NT3) with diminished affinity(26, 29). Though principally localized to central and peripheral nervous system tissues (26), isoform TrkB-T1 is also detected in the heart, kidneys, and pancreas (31). Extracellular ligand-binding induces autophosphorylation (32), promoting survival and neurodifferentiation (33), and mediation of synaptic plasticity(34, 35). NTRK2 exhibits great isoform complexity containing 24 exons (36) on chromosome 9 (37) producing at least 36 isoforms (31).

NTRK2 fusions contributing to human cancer have recently been detected. RNA-seq data from 7000 samples derived from The Cancer Genome Atlas uncovered previously characterized and novel NTRK2 fusions in low-grade gliomas (AFAP1-NTRK2), head and neck squamous cell carcinoma (PAN3-NTRK2) and lung adenocarcinoma (TRIM24-NTRK2)(18). A 2013 next-generation sequencing study of 96 pilocytic astrocytomas identified constitutively active kinase activity from novel NACC2:NTRK2 and QKI:NTRK2 fusions (19) in 3 of the 9 non-cerebellar tumors lacking other identified fusions. NTRK2 translocations also are oncogenic in neuroblastoma (38), ovarian, pancreatic, prostate, hepatocellular, and gastric cancers (reviewed in (39)).


NTRK3 was discovered in hippocampal cerebral cortex and granular cell layers of the cerebellum and binds NT3 but not BDNF or NGF (40). Subsequent analysis implied a role for NTRK3 in oncogenesis since high-level NTRK3 mRNA expression strongly correlates with challenging disease progression in medulloblastoma patients (41). NTRK3 translocations are characterized across many cancer types, including radiation-associated thyroid cancer (42), high grade gliomas (14), acute myeloid leukemia(43-45), ductal carcinoma(46-49), fibrosarcomas(50-52), congenital mesoblastic nephroma (53) and secretory breast carcinoma (54).

Of the relatively few gene fusions characterized with NTRK, translocation of NTRK3 and Ets family transcription factor 6 (ETV6) appears with the greatest frequency(42-44, 46-54). This fusion imparts the N-terminal pointed (PNT) domain mediating autooligomerization from ETV6 to the kinase domain of NTRK3, contributing to its autoactivation and transforming activity(45, 55-57).

Research on NTRK Tyrosine Kinase Inhibitors

Thyroid malignancies are strongly skewed towards papillary thyroid carcinomas (PTC), which compose as much as 80% of all cases (58). Seventy percent of PTC cases result from rearrangements of RET or NTRK and point mutations in RAS or BRAF (58). NTRK translocations generally result in constitutively active tyrosine kinase activity upregulating the Ras-Raf1-Mek1-Erk1/2 or PI3K-Akt pathways(16, 59). These in turn converge on the mitogen-activated protein kinase (MAPK) pathway, of which mutation in a single component may be sufficient to yield a malignant phenotype (60). Thus, targeting NTRK fusions constitutively activating the MAPK pathway is an appealing pharmacological possibility actively pursued by current research investigators.

Ongoing research studies address NTRK tyrosine kinase activity inhibition as a potential therapeutic target. Tyrosine kinase inhibitors ARRY-470, CEP-701, CEP-751 and crizotinib were shown to reduce NTRK autophosphorylation and downstream phosphorylation of AKT and ERK in Ba/F3 cells containing TFG-NTRK1 translocations, and may more broadly affect other NTRK family members(16, 61). CEP-701 is an orally active K252a analog in clinical evaluation for inhibition of tyrosine kinase receptors, suggested to be a potent tyrosine kinase inhibitor(9, 10). CEP-751 is an indolocarbozale derivative which modest growth inhibition effects against NTRK2-overexpressing tumors (62). ARRY-470 is a small-molecule NTRK1 inhibitor of nanomolar sensitivity originally employed to attenuate cancer pain (63). CEP-751 and ARRY-470 were shown more effective inhibitors of NTRK1 than crizotinib in lung cancer clinical samples(64, 65). Orally administrable AZ-23 has also shown early success at selectively inhibiting NTRK1 and NTRK2 (66), and selectively inhibited chimeric LMNA-NTRK1 autophosphorylation and activation of downstream AKT, ERK, S6, and PLC?1 pathways in melan-a cells (17).

Given these successes, it comes as no surprise that several clinical trials of TRK inhibitors have been initiated to target aberrant NTRK tyrosine kinase activity, including LOXO-101 (TRKA/B/C; NCT02122913) and Ignyta's phase II clinical trial of entrectinib, RXDX-101 (TRKA/B/C, ALK, ROS1; NCT02097810), both specifically targeting NTRK gene-fusion positive NSCLC patients (for a full list, see ClinicalTrials.gov: http://clinicaltrials.gov/ct2/results?term=TRKA&Search=Search). The advent of these potent NTRK inhibitors and the realization that NTRK translocations are found in increasing types of cancers highlights the need for ongoing research to detect and molecularly characterize NTRK1 translocations to promote future treatment options.

Table 3: Summary of NTRK fusions and associated disease types
Fusion Partner Disease PubMed Evidence
BCAN-NTRK1 Glioblastoma (67)
BCAN-NTRK1 Glioblastoma (15)
CD74-NTRK1 Lung adenocarcinomas (16)
LMNA-NTRK1 Spitzoid melanomas (17)
MPRIP-NTRK1 Lung adenocarcinomas (16)
NFASC-NTRK1 Glioblastoma (67)
NFASC-NTRK1 Glioblastoma (15)
RABGAP1L-NTRK1 Intrahepatic cholangiocarcinoma (ICC) (12)
TFG-NTRK1 Thyroid carcinomas (13)
TP53-NTRK1 Spitzoid melanomas (17)
TPM3-NTRK1 Papillary thyroid carcinomas (4, 68)
TPM3-NTRK1 Glioblastoma (14)
AFAP1-NTRK2 Low-grade glioma (18)
AGBL4-NTRK2 Glioblastoma (14)
NACC2-NTRK2 Pilocytic astrocytomas (19)
PAN3-NTRK2 Head and neck squamous cell carcinoma (18)
QKI-NTRK2 Pilocytic astrocytomas (19)
TRIM24-NTRK2 Lung adenocarcinoma (18)
VCL-NTRK2 Glioblastoma (14)
BTBD1-NTRK3 Glioblastoma (14)
ETV6-NTRK3 Glioblastoma (69)
ETV6-NTRK3 Secretory breast carcinoma (54)
ETV6-NTRK3 Ductal carcinoma (46-49)
ETV6-NTRK3 Fibrosarcoma (50, 51)
ETV6-NTRK3 Congenital mesoblastic nephroma (53)
ETV6-NTRK3 Radiation-associated thyroid cancer (42)
ETV6-NTRK3 Glioblastoma (14)
ETV6-NTRK3 Acute myeloid leukemia (AML) (43, 44, 52)
BCAN-NTRK1 Glioblastoma (67)

The Challenges of Translocation Discovery

Historically, NTRK fusions were discovered by cloning biologically active cDNAs from cell lines(1, 20, 26, 40). In the case of human samples, where both fusion partners are known, RT-PCR and qPCR probes can be generated to locate a predetermined fusion product (67). Fluorescence in-situ hybridization (FISH) assays, including fusion and break-apart probes, may subjectively describe the presence or absence of a fusion(46, 65).

Despite the plethora of methods used to detect gene translocations, discovery of novel partners using these methods is laborious, typically relying on primer-walking Sanger sequencing or whole exome sequencing. FISH assays require subjective analysis by trained experts, yet equivocal results are still common since processing slides may mechanically separate chromosomal regions betwixt different curls of the same sample. Varying degrees of natural chromosomal condensation may affect how far apart FISH probes hybridize, making fluorescent signals ambiguous. FISH, RT-PCR, and qPCR are all plagued by the common weakness of requiring very specific fusion locations in order to produce a result. Modern fusion-detection research relies heavily on next-generations sequencing technologies like whole genome sequencing, exome sequencing, and RNA-seq to locate novel fusions(14, 16, 18, 19, 64). These studies are laborious considering the magnitude of data accumulated for each research sample, and require significant bioinformatics resources to unravel.

Anchored Multiplex PCR enables better fusion sequencing

Targeted sequencing technologies hold promise for reducing the amount of data to interpret, but are challenged by the same caveat of RT-PCR and qPCR, namely the exact fusion loci must be known to generate primers for targeting. Anchored Multiplex PCR (AMP™) technology was designed to overcome this very situation by using half-functional Y-adapters of known sequence which are ligated to next-generation sequence libraries upstream of any polymerase chain reactions. In cases where novel fusions are present, a gene-specific primer (GSP) to NTRKs can amplify against a known adapter sequence, producing sequencing-ready targeted libraries under circumstances that previously would require whole-genome, exome, or RNA-seq to identify.

The Archer FusionPlex NTRK Kit includes assay-specific primers, reagents and lyophilized enzymes specific to either the Illumina® or Ion Torrent™ platform. You'll also need Molecular Barcoded Adapters (MBCs), provided separately. MBCs contain partially-functional Y-adapters and molecular barcode sequences permitting de-duplication of amplicon samples and molecular indices to distinguish multiple libraries run together in parallel.

Processing sequencing data procured from a library prepared using the Archer FusionPlex NTRK Kit is easily accomplished using the freely available Archer Analysis software to report tiered analysis indicating specific detected fusions and mutations with confidence, checking against a curated database of published fusions to add credibility to any detected translocations. Call your NTRK fusion results with confidence with the Archer FusionPlex NTRK Kit and Archer Analysis Pipeline.


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