cMyc and ERK activity are associated with resistance to ALK inhibitory treatment in glioblastoma

Berberich, Anne; Schmitt, Lara Marie; Pusch, Stefan; Hielscher, Thomas; Rübmann, Petra; Hucke, Nanina; Latzer, Pauline; Heßling, Bernd; Lemke, Dieter; Keßler, Tobias; Platten, Michael; Wick, Wolfgang

doi:10.1007/s11060-019-03348-z

Cited by 14 publications

(17 citation statements)

References 42 publications

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“…Preclinical research has however shown that EGFR inhibition combined with the inhibition of other pathways including PI3K, CK2, and JAK2 may potentially prevent drug resistance [25,101,122]. More new studies emerge that investigate combined therapies as a remedy to overcome resistance to kinase inhibitors within multiple tumorigenic pathways [11,64].…”

Section: Results and Discussion Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

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Targeting protein kinases for anti-glioma treatment

Pucko¹,

Ostrowski²

2020

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The genetic alterations related to many kinases are responsible for the formation of glial tumours. In addition it is the cell kinases that keep the cancerous signalling machinery in motion, thus enabling tumour cell growth, motility and invasion. Kinase inhibitors may have a potential to surpass the classical oncolytic treatment for gliomas. However, overcoming drug resistance mechanisms and limited blood-brain barrier (BBB) permeability are the remaining daunting issues. Latest research explores novel kinase inhibitors, yielding several promising results, including those from CK2 inhibition studies, as well as the possibility of relabelling the inhibitors previously approved for tumours other than glial tumours.

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Section: Results and Discussion Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

“…ALK is highly expressed among others in glioblastomas and WNT-activated medulloblastomas in paediatric populations, where it has been recommended as a valuable marker in routine investigations [56]. Hence, ALK inhibitors (alectinib) might be considered for treatment of selected brain tumours [11].…”

Section: Other Receptor Tyrosine Kinasesmentioning

confidence: 99%

Targeting protein kinases for anti-glioma treatment

Pucko¹,

Ostrowski²

2020

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“…ERK pathway is strongly associated with poor prognosis and glioblastoma patient survival [49]. In glioblastoma, ERK pathway has been reported to promote angiogenesis once activated by VEGF under hypoxia [49], to enhance drug resistance [50], and maintain high glutamine metabolism [51]. Similar to PI3K-Akt pathway, ERK signaling has also been considered as a therapeutic target of glioblastoma.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles Derived from Glioblastoma Promote Proliferation and Migration of Neural Progenitor Cells via PI3K-Akt Pathway

Pan

Sheng

et al. 2021

Preprint

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BackgroundGlioblastomas are lethal brain tumors under the current combinatorial therapeutic strategy that includes surgery, chemo- and radio-therapies. Extensive changes in the tumor microenvironment is a key reason for resistance to chemo- or radio-therapy and frequent tumor recurrences. Understanding the tumor-nontumor cell interaction in TME is critical for developing new therapy. Glioblastomas are known to recruit normal cells in their environs to sustain growth and encroachment into other regions. Neural progenitor cells (NPCs) have been noted to migrate towards the site of glioblastomas, however, the detailed mechanisms underlying glioblastoma-mediated NPCs’ alteration remain unkown. MethodsWe utilized two classic glioblastoma cell lines, U87- and A172, and collected EVs in the culture medium of those two lines. Mouse NPCs (mNPCs) were co-cultured with U87- or A172-derived EVs. EVs-treated mNPCs’ prolifeartion and migration were examined. Proteomic analysis and western-blot were utilized to identify the underlying mechanisms of glioblastoma EVs-induced alterations in mNPCs.ResultsWe show that glioblastoma cell lines U87- and A172-derived EVs dramatically promoted NPCs proliferation and migration. Mechanistic studies identify that EVs achieve their functions via activating PI3K-Akt-mTOR pathway in recipient cells. Inhibiting PI3K-Akt reversed the elevated prolfieration and migration of glioblastoma EVs-treated mNPCs. ConclusionOur findings demonstrate that EVs play a key role in intercellular communication in tumor microenvironment. Inhibition of the tumorgenic EVs-mediated PI3K-Akt-mTOR pathway activation might be a novel strategy to shed light on glioblastoma therapy.

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“…Previous studies have reported that ALK expression levels in GBM cell lines are generally low. [18][19][20] Therefore, the question was asked how ALK was expressed and activated in the GBM cells used in this study. To determine this, ALK mRNA and protein levels in the three GBM cell lines used in the above experiments were investigated.…”

Section: Alk Expression In Human Gbm Cells Was Substantially Lowmentioning

confidence: 99%