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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 5 of 17

Oncogenic gene fusions are somatic genetic alteration caused by interchromosomal translocation,
[23]
intrachromosomal translocation, insertion, deletion, tandem duplication, inversion, chromothripsis , and
[24]
read-through . The first identified cancer-causing fusion gene is BCR-ABL gene, product of a reciprocal
interchromosomal translocation between the q arms of chromosomes 9 and 22 that occurs in more than
[25]
96% of patients with CML . The first fusion gene in epithelial solid tumors, rearranged during transfection
[26]
(RET)-CCDC6, was found in papillary thyroid carcinoma more than 30 years ago . Since then, many gene
fusions have been discovered, facilitated by large scale sequencing efforts such as those championed by The
Cancer Genome Atlas (TCGA), International Collaboration for Clinical Genomics (ICCG), International
Cancer Genome Consortium (ICGC), and numerous other institutional studies. With the technological
advancement in detection methods, the identity of gene rearrangement partners, the spectrum of tumor
histologies where the gene rearrangements have been found, and their overall prevalence have significantly
expanded in the past few years.

For instance, a recent study by Gao et al. interrogated 9,624 samples belonging to 33 cancer types in the
[27]
TCGA collection and identified 25,664 distinct fusion events. Importantly, among all fusions involving
receptor and non-receptor kinases, 1,275 cases contain an intact kinase domain, many of which are believed
to be the sole onco-driver in a particular tumor biopsy. Many of these fusion events lead to constitutive
activation of the kinase activity and downstream signaling pathways including mitogen-activated protein
kinase (MAPK) and phosphoinositide 3-kinase (PI3K) cascades, which enables cells to hyper-proliferate
and evade apoptosis [28-30] [Figure 2]. The mechanisms of activation include overexpression of the kinase as
a result of the activity of the promoter of the fusion partner, constitutive ligand-independent dimerization
of the fusion kinase proteins, and release of kinase auto-inhibitory mechanism. Since kinases are generally
druggable targets, studies such as this provided the rationale for developing small molecule targeted
therapies to treat fusion-driven hematological and solid tumors [31-34] .

THE LONG-TAIL PHENOMENON AND TISSUE-AGNOSTIC DEVELOPMENT
Although conceivably, specific drugs can be developed to address these distinct fusion proteins in each of
the tumor types involved individually, in reality, with the exception of a few cases, such as ALK and ROS1
fusions in NSCLC and fibroblast growth factor receptor (FGFR) fusions in cholangiocarcinoma , the
[36]
[35]
[37]
majority of the fusions occur at low frequencies . The low and ultra-low frequency alterations sometimes
are called the “long tail” . As discussed above, the rarity of the fusions and the resulting small patient pool
[38]
make the development of a particular targeted drug for a single tumor type impractical.
One potential solution to address this challenge lies in the observation that a number of recurring gene
fusions, such as those formed by ALK, ROS1, FGFR, NTRK, and RET, have been identified in multiple
[40]
[39]
cancer histologies. For example, ALK fusions are found in anaplastic large cell lymphoma , NSCLC ,
[42]
[41]
[44]
[43]
papillary thyroid cancer , colorectal cancer , renal cell cancer , and esophageal cancer , as well as in
[45]
spitzoid tumors . Similar to ALK fusions, FGFR fusions have been reported in a wide range of tumors
such as cholangiocarcinoma, breast cancer, prostate cancer, NSCLC, gastric adenocarcinoma, colorectal
[46]
adenocarcinoma, and glioblastoma, with a large number of distinct fusion partners . The long-tail
phenomena (rare and ultra-rare patient populations) and recurring fusions across multiple tumor types
necessitate biomarker-driven cross-tumor type clinical trials, to enroll a sufficient number of patients
for efficacy and safety assessment and to offer patients with a rare actionable mutation access to an
experimental therapy.
TRK
The tyrosine kinase receptors TRKA, TRKB, and TRKC, are encoded by neurotrophic tropomyosin receptor
kinase (NTRK) genes NTRK1, NTRK2, and NTRK3, respectively. Their ligands are neurotrophins, a family