Page 61 - GTM-1-1

Global Translational Medicine Fusion events identified in tumor

MET and STAT3 signaling, followed by tumor-associated PLB-1001 has higher permeability and lower efflux rate.
macrophage recruitment, which contribute to tumor On the other hand, the in vivo analysis demonstrated
malignancy . Some rare but recurrent fusion events, that PLB-1001 treatment significantly reduce the growth
[83]
including ROS1 and PTPRZ1-ETV1 fusion, were also of ZM-harboring xenografts as compared to Crizotinib
identified in adult glioma patients [84,85] . MET fusion is the and vehicle treatments. Interestingly, a deep learning
least common RTK fusion in pediatric CNS neoplasms. model that combines with the application of computed
CLIP2-MET, TFG-MET, and PTPRZ1-MET fusions tomography image for predicting ALK fusion status and
have been reported in pediatric CNS tumors with the response to TKI therapy in non-small cell lung cancer
kinase domain of MET retained. The CLIP2-MET and patients provides a novel strategy for investigating the
[98]
TFG-MET fusion proteins retain only the C-terminal response of TKI targeting the fusion transcripts.
part of the fusion and lack the domain that facilitates
the activation of MET pathway . In addition, TFG has 7. Clinical trials targeting fusion events
[86]
also been reported as a counterpart for fusing with MET The chromosomal instability in gliomas and other solid
in chimeric proteins . In addition to the MET fusion tumors leads to tumor heterogeneity and structural
[87]
[99]
proteins, all patients possessed CDKN2A and CDKN2B variations, including exon skipping, fusion transcripts
deletions and/or TP53 mutations, indicating that the and chromothripsis, which are maintained by the
oncogenic potentials due to MET fusions are probably selective pressure from a broad-spectrum approach
dependent on additional genomic or transcriptomic involving chemotherapy and other targeted treatments
[77]
alterations in the cell cycle regulation . that might provide the direction of further treatment
6. Fusion gene targeted therapy in cancer and solve the problem of tumor heterogeneity and drug
resistance. Despite some clinical trials that target fusion-
The development of fusion gene-targeted therapy strategies induced tumor malignancy, most of these clinical trials
generally focuses on either the chimeric protein or one focused on DNA-based rearrangement rather than fusion
of the fusion proteins. Most fusion genes consist of one transcripts generated by alternative splicing. Various
tyrosine kinase at least at the end of fusion protein. Hence, clinical trials focused on ALK , RET [100] , FGFR, [101]
[52]
tyrosine kinase inhibitors (TKI) are frequently chosen to and ROS1 [102] fusion-positive patients with lung cancer
inhibit fusion-induced tumor malignancy [88,89] . TRK fusions showed that progression-free survival and overall survival
are oncogenic drivers of various adult and pediatric tumors. were prolonged after the patients were administered with
An intracranial activity has been recently reported in TRK fusion-targeted TKIs. Larotrectinib and Selitrectinib
inhibitor-treated patients with TRK fusion-positive solid had marked and durable antitumor activity in patients
tumors, specifically with brain metastases and primary with TRK fusion-positive solid tumors, regardless of the
brain tumors [90,91] . ROS1, NTRK, and FGFR inhibitor tumor type (Table 1) [103-106] . However, there has been no
have been selected to treat patients with different types breakthrough in the development of drug intervention for
of cancer, respectively [92-94] . In addition, the combination MET-induced genetic variation, including MET fusion
of selpercatinib and crizotinib has been administered and exon skipping in glioma and other types of cancer.
to RET fusion-positive lung cancer patients who were In a Phase I, open-label study (NCT02978261), PLB-1001
resistant to RET inhibitor as a result of MET fusion . was orally administered to recurrent high-grade glioma
[95]
Similar fusion event, BRAF fusion, has been recognized as patients with ZM fusion and/or METex14. Out of the six
a novel mechanism of acquired resistance to vemurafenib enrolled secondary GBM patients, two achieved partial
in BRAFV600E mutant melanoma . Fusion events are response, two in stable disease, and two in progressed
[96]
probably the mechanisms of TKI resistance, which could be disease with no severe adverse events; this finding
treated using alternative or combined therapeutic strategies. indicates the potential inhibitory effect of PLB and help
Of note, it has been reported that structural alterations determine the dose required for further investigation in
[83]
of MET responded to MET inhibition in lung cancer Phase II clinical trial . The median overall survival of
[97]
patients . Hu et al. described a highly selective ATP- the patients increased from 183 days to 466 days, and
competitive small-molecule MET inhibitor known the 1-year survival rate increased from 8% to 67% [107] .
as PLB-1001, which has been shown to improve More in-depth mechanism studies, identification of
selectivity compared with Crizotinib (a well-known more targets, and more Phases 2 and 3 clinical trials are
targeted inhibitor for glioma treatment) and inhibit urgently needed. We have identified MET fusion in brain
the phosphorylation of MET and STAT3 . Based on metastases, which may mark the start of investigating the
[83]
their in vitro analysis results, compared to other MET use of MET inhibitors on MET fusion-positive patients
inhibitors such as Crizotinib, Cabozantinib, and Foretinib, with different types of cancer from bench to clinic.

Volume 1 Issue 1 (2022) 6 https://doi.org/10.36922/gtm.v1i1.54