Gene Fusion in Malignant Glioma: An Emerging Target for Next-Generation Personalized Treatment

Xu, Tao; Wang, Hongxiang; Huang, Xuanjing; Li, Weiqing; Huang, Qilin; Yan, Yongmin; Chen, Juxiang

doi:10.1016/j.tranon.2018.02.020

Cited by 45 publications

(36 citation statements)

References 97 publications

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“…The various downstream signalling targets of this molecule such as PI3K/AKT have already been mentioned above. This work showed augmented levels of FGFR1 in the resistant lines that were in lieu of a recent study that showed similar up‐regulation in U87/TR cells . FGFR1 has also been shown to be oncogenic in the case of glioma by modulating the ability of cells to divide, migrate and invade .…”

Section: Discussionsupporting

confidence: 75%

MiR‐3116 sensitizes glioma cells to temozolomide by targeting FGFR1 and regulating the FGFR1/PI3K/AKT pathway

Kong

Cao

et al. 2020

J Cellular Molecular Medi

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| 4677 wileyonlinelibrary.com/journal/jcmm | INTRODUC TI ONGlioma accounts for 30% of brain tumours and 80% malignancies making it a ubiquitous malignancy of the brain. 1,2 While there have been developments to address this condition, the median survival is 12-14 months for the high-grade disease causing the prognosis. 3 One approach is the use of chemotherapy (temozolomide: TMZ) plus surgery and radiotherapy. This approach, however, is challenged by TMZ resistance (inherent and acquired). 4,5 This calls for the addressing of this condition to boost the responses of the malignancy to TMZ. MicroRNAs (MiRNAs) are the small endogenous non-coding RNAs that could inhibit translation or degrade mRNA by base-pairing to the 3′-untranslated region (UTR) of targets to result in the inactivation of the latter. 6,7 Research has shown that miRNAs are oncogenes or tumour suppressors by targeting the cell cycle, cell division, apoptosis and angiogenesis in numerous human cancers. 8 There is also proof of the functioning of miRNAs in the resistance to chemotherapeutic AbstractGlioma is a brain tumour that is often diagnosed, and temozolomide (TMZ) is a common chemotherapeutic drug used in glioma. Yet, resistance to TMZ is a chief hurdle towards curing the malignancy. The current work explores the pathways and involvement of miR-3116 in the TMZ resistance. miR-3116 and FGFR1 mRNA were quantified by real-time PCR in malignant samples and cell lines. Appropriate assays were designed for apoptosis, viability, the ability to form colonies and reporter assays to study the effects of the miR-3116 or FGFR1. The involvement of PI3K/AKT signalling was assessed using Western blotting. Tumorigenesis was evaluated in an appropriate xenograft mouse model in vivo. This work revealed that the levels of miR-3116 dipped in samples resistant to TMZ, while increased miR-3116 caused an inhibition of the tumour features mentioned above to hence augment TMZ sensitivity. miR-3116 was found to target FGFR1. When FGFR1 was overexpressed, resistance to TMZ was augmented and reversed the sensitivity caused by miR-3116. Our findings further confirmed PI3K/AKT signalling pathway is involved in this action. In conclusion, miR-3116 sensitizes glioma cells to TMZ through FGFR1 downregulation and the PI3K/ AKT pathway inactivation. Our results provide a strategy to overcome TMZ resistance in glioma treatment. K E Y W O R D Sdrug resistance, FGFR1, FGFR1/PI3K/AKT, miR-3116, temozolomide

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Section: Discussionsupporting

confidence: 75%

MiR‐3116 sensitizes glioma cells to temozolomide by targeting FGFR1 and regulating the FGFR1/PI3K/AKT pathway

Kong

Cao

et al. 2020

J Cellular Molecular Medi

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“…Gene fusions involving NTRK1, NTRK2 or NTRK3 (encoding TRKA, TRKB and TRKC, respectively) occur at varying frequencies in GBM, with NTRK2 fusions the most commonly observed (up to 11% of GBM). NTRK1 and NTRK3 are observed in <1% of cases, 107,108 These NTRK fusions drive ligand-independent activation of the TRK, resulting in activation of a variety of downstream cascades including RAS/RAF/MEK/ERK and PI3K/AKT pathways, ultimately promoting tumour cell proliferation and survival. 109 To date, it has been shown that overexpression of the neurofascin (NFASC)-NTRK1 fusion gene in NIH 3T3 cells increases cell proliferation, colony formation and tumour formation in a xenograft model.…”

Section: Neurotrophic Tropomyosin Receptor Kinase Fusions and Braf Almentioning

confidence: 99%

New hints towards a precision medicine strategy for IDH wild-type glioblastoma

et al. 2020

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Glioblastoma represents the most common primary malignancy of the central nervous system in adults and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wild-type setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wildtype glioblastoma setting, and propose an integrated discovery stratagem incorporating multi-omics, single-cell technologies and computational approaches.

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“…Oncogenic NTRK fusions with various partner genes result in chimeric receptor kinase proteins that lead to an uncontrolled activation of the tyrosine kinase signaling pathway. NTRK fusions are encountered in 2 categories of tumors; at a high frequency in some rare cancers such as secretory carcinoma of the salivary gland, secretory breast carcinoma, congenital mesoblastic nephroma, and infantile fibrosarcoma, 4‐8 and at a lower frequency in more common cancers, including thyroid cancer 9‐18 . However, NTRK fusions are found at a higher frequency in certain PTC populations, reaching as high as 26% in pediatric PTC patients and 10% to 15% in postradiation PTC patients 17,19‐22 …”

Section: Introductionmentioning

confidence: 99%

Fine‐needle aspiration cytomorphology of papillary thyroid carcinoma with NTRK gene rearrangement from a case series with predominantly indeterminate cytology

Abi‐Raad

Prasad

Adeniran

et al. 2020

Cancer Cytopathology

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Background Neurotrophic tyrosine kinase receptor (NTRK) rearrangement has been reported in a subset of papillary thyroid carcinoma (PTC) cases. Little is known about the cytomorphologic features of NTRK‐rearranged PTC. Methods We report an institutional series of 13 fine‐needle aspiration (FNA) specimens of NTRK‐rearranged PTC with a predominantly indeterminate cytology diagnosis. NTRK3 or NTRK1 rearrangements were detected on FNA or surgical specimens by next‐generation sequencing. Results The 13 patients had a median age of 18 years; 10 patients were female and 3 patients were male. In 10 (77%) cases, cytology was indeterminate, and histopathologic follow‐up was predominantly the follicular variant of PTC (n = 8 [62%]), mostly infiltrative subtype. Of 12 FNA specimens available for review, a predominant loosely cohesive group pattern was the most commonly encountered architectural pattern (n = 5 [41%]), followed by single cell (n = 3 [25%]), thick cord (n = 2 [17%]), and microfollicular pattern (n = 2 [17%]). Background lymphocytic thyroiditis was observed in 9 cases. At the cellular level, the cytoplasm was moderate and granular, occasionally vacuolated. Classic PTC nuclear features (eg, nuclear enlargement, elongation, grooves, and nuclear membrane irregularity) were present but were often focal and subtle. Chromatin was often granular. Intranuclear pseudoinclusions were absent or rare. Conclusion Our study demonstrates that most cases of NTRK rearrangement lack classic PTC cytomorphologic characteristics. Loosely cohesive groups and single cells with granular, sometimes vacuolated cytoplasm and subtle nuclear features are often seen on FNA specimens. Recognizing these characteristics may be helpful to preoperatively prompt molecular testing, including NTRK rearrangement analysis.

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Gene Fusion in Malignant Glioma: An Emerging Target for Next-Generation Personalized Treatment

Cited by 45 publications

References 97 publications

MiR‐3116 sensitizes glioma cells to temozolomide by targeting FGFR1 and regulating the FGFR1/PI3K/AKT pathway

MiR‐3116 sensitizes glioma cells to temozolomide by targeting FGFR1 and regulating the FGFR1/PI3K/AKT pathway

New hints towards a precision medicine strategy for IDH wild-type glioblastoma

Fine‐needle aspiration cytomorphology of papillary thyroid carcinoma with NTRK gene rearrangement from a case series with predominantly indeterminate cytology

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