ArticleJournal of neuro-oncology2020
cMyc and ERK activity are associated with resistance to ALK inhibitory treatment in glioblastoma.
Article in Journal of neuro-oncology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 16 citations in OpenAlex.
- Molecularly matched targeted therapies plus radiotherapy in glioblastoma: the phase 1/2a NNature medicine · 2025Trial
- Altered perivascular diffusivity in glioblastoma: integrating DTI-ALPS index with radio-pathomic and histopathologic correlates.Journal of neuro-oncology · 2026Article
- Altered Perivascular Diffusivity in Glioblastoma:Integrating DTI-ALPS Index with Radio-Pathomicand Histopathologic Correlates.Research square · 2025Article
- Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment.International journal of molecular sciences · 2024Review
- Evaluation of Immunohistochemical Expression of ALK-1 in Gliomas, WHO Grade 4 and Its Correlation with IDH1-R132H Mutation Status.Asian Pacific journal of cancer prevention : APJCP · 2024Article
- Effects of postoperative radiotherapy and docetaxel and PD-1 inhibitors on the survival and safety of glioblastoma patients: a systematic review and meta-analysis.Annals of translational medicine · 2022Article
- Extracellular vesicles derived from glioblastoma promote proliferation and migration of neural progenitor cells via PI3K-Akt pathway.Cell communication and signaling : CCS · 2022Article
- IP-Se-06, a Selenylated Imidazo[1,2-Oxidative medicine and cellular longevity · 2022Article
- Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma.Cancers · 2021Article
- The ALK inhibitors, alectinib and ceritinib, induce ALK-independent and STAT3-dependent glioblastoma cell death.Cancer science · 2021Article
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
backgroundAnaplastic lymphoma kinase (ALK) is expressed in ~ 60% of glioblastomas and conveys tumorigenic functions. Therefore, ALK inhibitory strategies with alectinib are conceivable for patients with glioblastoma. The aims of this preclinical study were to investigate efficacy as well as to understand and potentially overcome primary and acquired resistance mechanisms of alectinib in glioblastoma.
methodsEfficacy of alectinib was analyzed dependent on ALK expression in different glioblastoma initiating cells and after lentiviral knockdown of ALK. Alectinib resistant cells were generated by continuous treatment with increasing alectinib doses over 3 months. M-RNA, phospho-protein and protein regulation were analyzed to decipher relevant pathways associated to treatment or resistance and specifically inhibited to evaluate rational salvage therapies.
resultsAlectinib reduced clonogenicity and proliferation and induced apoptosis in ALK expressing glioblastoma initiating cells, whereas cells without ALK expression or after ALK depletion via knockdown showed primary resistance against alectinib. High expression of cMyc and activation of the ERK1/2 pathway conferred resistance against alectinib in ALK expressing glioblastoma cells. Pharmacological inhibition of these pathways by cMyc inhibitor or MEK inhibitor, trametinib, overcame alectinib resistance and re-sensitized resistant cells to continued alectinib treatment. The combination of alectinib with radiotherapy demonstrated synergistic effects in inhibition of clonogenicity in non-resistant and alectinib resistant glioblastoma cells.
conclusionThe data offer rationales for alectinib treatment in ALK expressing glioblastoma and for the use of ALK expression status as potential biomarker for alectinib treatment. In addition, the results propose MEK inhibition or radiotherapy as reasonable salvage treatments after acquired alectinib resistance.
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