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Page 8 of 17 Li et al. J Cancer Metastasis Treat 2020;6:14 I http://dx.doi.org/10.20517/2394-4722.2020.27

and provide the driving force for transformation and tumor progression; and (2) regardless of the identity
of the fusion partners, TRK inhibitors such as entrectinib exhibit similar anti-tumor potency in cell lines
harboring NTRK1, NTRK2, or NTRK3 fusion genes (i.e., TPM3-NTRK1, LMNA-NTRK1, SQSTM1-NTRK1,
BCAN-NTRK1, MPRIP-NTRK1, AFAP1-NTRK2, VCL-NTRK2, and ETV6-NTRK3), and in NTRK-fusion-
positive xenograft models derived from various tumor types. For instance, tumor growth inhibition was
observed in cancer cell line-derived xenograft models of CRC harboring TPM3-NTRK1 fusion, AML
harboring ETV6-NTRK3 fusion, and NSCLC harboring MPRIP-NTRK1 fusion, as well as in patient-
derived xenograft (PDX) models of metastatic CRC harboring LMNA-NTRK1 fusion, head and neck cancer
[67]
harboring ETV6-NTRK3 fusion, and sarcoma harboring TPM3-NTRK1 fusion .

As discussed above, the preclinical observations have been clinically validated in several clinical trials that
led to the regulatory approvals of larotrectinib and entrectinib as the first two small molecule anti-cancer
drugs that carry a tissue-agnostic label.

ROS1
ROS1 belongs to the insulin-receptor superfamily of receptor tyrosine kinases and plays a role in relaying
growth signals from the environment outside the cell into the cell’s nucleus. It is an orphan receptor
tyrosine kinase with no known binding ligand. Genetic changes in ROS1, such as gene rearrangements,
[68]
mutations, or copy number increases, create oncogenes that can lead to cancer . ROS1 gene
rearrangements create fusion proteins with constitutively active kinase domains that activate downstream
signaling pathways leading to oncogenic properties in cells, including uncontrolled proliferation and
resistance to cell death with prolonged tumor cell survival. These pathways include Ras-ERK for cellular
proliferation and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) and PI3K/
AKT pathways, which regulate cell survival (anti-apoptosis) and proliferation. ROS1 fusion proteins may
also activate the mammalian target of the rapamycin pathway, which is critical for the regulation of protein
translation. Cancers that have these pathways activated tend to be more aggressive, with invasion and
[69]
metastasis leading to poor patient survival .
In NSCLC patients, ROS1 fusion protein is found in approximately 1%-2.5% of patients [70,71] . ROS1 gene
rearrangements have also been detected in a variety of other cancers, including glioblastoma multiforme [72,73] ;
[74]
[76]
[75]
biliary tract carcinoma (3.9%) ; ovarian cancer, gastric adenocarcinoma (0.61%) ; CRC (0.85%) ;
inflammatory myofibroblastic tumor, angiosarcoma, and epithelioid hemangioendothelioma [69,70,75,77] ;
and Spitz nevus (benign) (25.3%), atypical Spitz tumors (6.2%), and spitzoid melanomas (9.1%) .
[45]
Thus far, more than two dozen N-terminal fusion partners have been identified . All the fusion proteins
[78]
[79]
retain the ROS1 kinase domain, but rarely its transmembrane domain . The most common ROS1 fusion
[80]
partner is CD74 . Other commonly observed ROS1 fusion partners include SDC4, SLC34A2, LRIG3,
EZR, and TPM3 [77,78] . A survey of cBioPortal for Cancer Genomics (https://www.cbioportal.org) and The
Cancer Genome Atlas (TCGA) generated the following breakdown of ROS1 fusion partners: 38% CD74,
12% EZR, 12% SLC34A2, 9% SDC4, 6% CEP85L, 6% GOPC, and rare cases of CLTC, GOLGB1, SLC4A4,
TFG, TMEM181, and TPM3. More than half of the partners have dimerization domains that are retained
in the fusion, presumably leading to constitutive ROS1 tyrosine kinase activation. Additional mechanism
of activation of the ROS1 fusion proteins may include removal of the auto-inhibitory domain from the full-
[69]
length ROS1 as the result of the fusing event . Recent survey of responses to crizotinib in 106 NSCLC
patients with ROS1 fusions of various fusion partners (49.1% CD74, 17% EZR, 14.2% SDC4 and 4.7%
TPM3) showed no significant difference among patients with various types of ROS1 fusion partners in
overall survival (OS) and progression-free survival (PFS) .
[81]
Clinically, multiple ROS1 inhibitors have been approved for ROS1-fusion-positive NSCLC. Although the
clinical efficacy of ROS1 inhibitors has not been systemically established, several preclinical studies have