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Li et al. J Cancer Metastasis Treat 2020;6:14 I http://dx.doi.org/10.20517/2394-4722.2020.27 Page 7 of 17

and activation of downstream signaling cascades. Physiologically, the TRK family members play a key role
in normal central and peripheral neuronal cell development and differentiation. NTRK gene mutations,
overexpression, splice variants, and fusions/rearrangements have been found in a number of human cancer
[48]
types .
The first NTRK gene fusion, TPM3-NTRK1, was identified in a colon carcinoma biopsy through
[49]
a transformation assay . Subsequently, TPM3-NTRK1 has been identified in additional CRC
[50]
[53]
tumors , sarcoma , lipofibromatosis-like neural tumors , spitzoid melanoma , invasive mucinous
[52]
[51]
[55]
[54]
adenocarcinoma of the lung , and papillary thyroid carcinoma . With the use of advanced molecular
diagnostic techniques, additional NTRK1 fusion partners have been identified in various tumor types, with 5’
[56]
fusion partners including LMNA, SQSTM1, BCAN, CD74, IRF2BP2, MDM4, MPRIP, and others .
Similarly, oncogenic fusions have also been identified with NTRK2 and NTRK3 genes, as well as across a
variety of cancer histologies. For example, NTRK2 forms fusions with partners such as AGBL4, NACC2,
QKI, and VCL, which were identified in non-brainstem high-grade glioma, soft tissue liposarcoma, head
and neck squamous cell carcinoma, pilocytic astrocytoma, ganglioglioma, and diffuse intrinsic pontine
glioma. NTRK3 fusion partners include ETV6, BTBD1, and EML4, which were identified in diffuse
intrinsic pontine glioma, congenital fibrosarcoma, papillary thyroid carcinoma, mammary analog secretory
carcinoma (MASC) of the thyroid gland, secretory breast cancer, and inflammatory myofibroblastic
tumor [48,57-60] , as well as in hematological malignancies such as acute myeloid leukemia, Philadelphia-like
acute lymphoblastic leukemia, and chronic eosinophilic leukemia [61-63] .

NTRK gene fusions have also been reported in pediatric solid tumors. For instance, oncogenic gene
fusions involving the NTRK3 kinase domain have been identified in congenital fibrosarcoma and pediatric
[57]
mesoblastic nephroma and acute leukemias . A survey of 2 pediatric cancer databases, St. Jude pediatric
cancer database (PeCan; total n = 1,604) and the University of Michigan database (Peds-MiOncoSeq; total
n = 91) resulted in the identification of three gene rearranged-cancers, one each involving NTRK1, NTRK2,
and NTRK3 in a sarcoma, a low-grade glioma, and a B-cell acute lymphoblastic leukemia, respectively.
In addition, the following tumor types, which are largely confined to the pediatric patient population, are
also known to harbor NTRK gene fusions: congenital or infantile fibrosarcoma, secretory (juvenile) breast
[64]
cancer, mesoblastic nephroma, and intrinsic pontine gliomas .

Fusion of 3’ NTRK gene sequences encoding the tyrosine kinase domain to various 5’ partner sequences
via intra- or inter-chromosomal rearrangement results in an oncogenic chimera protein that can ligand-
independently homodimerize, autophosphorylate, and constitutively activate downstream signaling
pathways, such as MAPK, PI3K/protein kinase B (AKT), and phospholipase C (PLC)-ɣ, which can result
in hyperproliferation and cell survival in tumors expressing these proteins. The growth of cancer cells thus
becomes dependent on or “addicted” to this abnormal kinase signaling .
[65]
Although oncogenic NTRK gene fusions are observed across a large number of adult and pediatric solid
and hematological tumors, they are rare events in most common cancers (e.g., frequency of < 0.1% in
NSCLC or CRC). Although much higher frequencies of NTRK fusions are present in certain tumor types
such as MASC, these cancers are ultra-rare, collectively representing less than 1% of all malignancies. As a
[66]
result, the overall population of NTRK-fusion-positive patients is very small .
The rarity of the molecularly defined patients and the vastly diverse histologies of the patients clearly called
for an innovative, tissue-agnostic approach. Fortunately, data generated in preclinical studies provided
[56]
rationale to perform tissue-agnostic clinical trials in multiple molecularly defined cancers : (1) regardless
of the fusion partner or the tissue of origin, the NTRK gene fusions result in a constitutively active kinase