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shown support of potential broad efficacy across tumor types that are driven by ROS fusion. For instance,
[73]
Davare et al. showed that CEP85L-ROS1 and GOPC-ROS1 are transforming oncogenes in cells of
astrocytic lineage, and they are sensitive to pharmacologic inhibition with several ROS1 inhibitors in vitro.
Furthermore, systemic therapy with a BBB-penetrant ROS1 inhibitor, lorlatinib, significantly prolonged
survival in an intracranially xenografted, ROS1-fusion-positive glioblastoma tumor model. In a separate
[82]
study , ROS1 inhibitors were able to inhibit FIG-ROS-driven cholangiocarcinoma in vitro and in vivo.
These data provide the rational support to a potential tissue-agnostic approach for treating ROS1-fusion-
positive cancers.

ALK
ALK belongs to the insulin-receptor superfamily and aberrant ALK fusion proteins lead to self-activation
and constitutive activity within cancer cells via activation of signal transduction pathways and intracellular
kinases that drive uncontrolled tumor cell growth, metabolism, and survival . In addition to anaplastic
[83]
lymphomas (ALCL), ALK oncogenes are found in a number of cancers such as NSCLC, diffuse large B-cell
lymphoma, neuroblastomas, colorectal cancer, inflammatory myofibroblastic tumors (IMT), esophageal/
gastric cancers, and renal cell cancers [35,83] . The currently available ALK inhibitor drugs, crizotinib, ceritinib,
[84]
alectinib, and brigatinib, have demonstrated clinical benefit in NSCLC . In a recent report based on the
[85]
CREATE Study in eight European countries, Schoffski et al. showed that, in ALK-fusion-positive IMT,
crizotinib treatment resulted in 50% ORR (6 responders out of 12 patients) with nine-month median
duration of response and 73% one-year PFS. On the contrary, the ORR was 14% (one out of seven) in ALK-
negative IMT. In addition to the CREATE study, similar or higher ORRs were observed in ALK-fusion-
positive patients enrolled in studies COG and PROFILE 1013. These two studies also demonstrated ORRs
of 53%-88% in ALCL.

FGFR
The FGFR protein family consists of four highly conserved transmembrane receptor tyrosine kinases
(FGFR1-4). Receptor activation by the fibroblast growth factor (FGF) ligands or oncogenic alterations
leads to intracellular signaling to promote cell proliferation, differentiation, morphogenesis and patterning,
[86]
angiogenesis, and survival . The FGFR signaling pathway is aberrantly activated in multiple types of
human cancers through various molecular alterations including point mutations, gene amplification
and overexpression, and chromosomal rearrangements/translocations. Many of these changes lead to
constitutive receptor activation and upregulation of the downstream signaling pathways, leading to
uncontrolled cell proliferation, survival, and migration, which are hallmarks of cancer. Both the overall
frequency of FGFR alterations and the relative distribution of the types of alterations vary by cancer
type [46,87,88] .

FGFR fusions are the result of gene rearrangements and have been detected in different types of human
cancers [46,89] [Table 1]. Particularly, FGFR2 fusions with different partners, such as BICC1, TACC3, CCDC6,
and AHCYL1, have been detected in approximately 10%-20% of intrahepatic cholangiocarcinomas [90-92] .
Lower frequencies of FGFR1-3 fusions have also been detected in breast cancer, bladder cancer,
glioblastoma, head and neck squamous cell carcinoma, low-grade glioma, lung adenocarcinoma, lung
squamous cell carcinoma, ovarian cancer, prostate adenocarcinoma, and thyroid carcinoma [46,87,88,93] . FGFR
fusion partners generally contain dimerization or oligomerization domains that lead to ligand-independent
[88]
constitute activation of the receptor and downstream RAS-MAPK and JAK-STAT signaling pathways ,
resulting in uncontrolled cell proliferation, survival, and migration, which are hallmarks of cancer. In solid
tumors, these FGFR fusions are typically formed by fusing near full-length FGFR with intact kinase domain
at the N-terminus and various fusion partners at the C-terminus (Type II fusions), suggesting that these
may serve as potential therapeutic targets via kinase inhibition. However, it is also possible for the fusion to