ArticlePloS one2018
PIK3CA missense mutations promote glioblastoma pathogenesis, but do not enhance targeted PI3K inhibition.
Article in PloS one, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 23 citations in OpenAlex.
- Potential Association of BRAF and PIK3CA Copy Number Alterations with Long-Term Survival in IDH-Wildtype Glioblastoma: A Pilot Study.International journal of molecular sciences · 2026Article
- Identifying and exploiting combinatorial synthetic lethality by characterizing adaptive kinome rewiring of EGFRvIII-driven glioblastoma.Acta neuropathologica communications · 2025Article
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- Arginines of the CGN codon family are Achilles' heels of cancer genes.Scientific reports · 2024Article
- Potential Diagnostic and Clinical Significance of Selected Genetic Alterations in Glioblastoma.International journal of molecular sciences · 2024Review
- Recent advances in label-free optical, electrochemical, and electronic biosensors for glioma biomarkers.Biomicrofluidics · 2023Review
- Environmental and sex-specific molecular signatures of glioma causation.Neuro-oncology · 2022Article
- TheEvidence-based complementary and alternative medicine : eCAM · 2022Article
- Potential Diagnostic Value of the Differential Expression of Histone H3 Variants between Low- and High-Grade Gliomas.Cancers · 2021Article
- Fishing for Contact: Modeling Perivascular Glioma Invasion in the Zebrafish Brain.ACS pharmacology & translational science · 2021Article
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- The Personalisation of Glioblastoma Treatment Using Whole Exome Sequencing: A Pilot Study.Genes · 2020Article
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- Prediction of regulatory targets of alternative isoforms of the epidermal growth factor receptor in a glioblastoma cell line.BMC bioinformatics · 2019Article
- PI3K/AKT/mTOR Pathway Alterations Promote Malignant Progression and Xenograft Formation in Oligodendroglial Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- Mutation profiling of anaplastic ependymoma grade III by Ion Proton next generation DNA sequencing.F1000Research · 2019Article
- Molecular and Clinical Insights into the Invasive Capacity of Glioblastoma Cells.Journal of oncology · 2019Review
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12 authors at 1 institution in 1 country.
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Abstract
backgroundGlioblastoma (GBM) is the most common adult primary brain tumor. Multimodal treatment is empiric and prognosis remains poor. Recurrent PIK3CA missense mutations (PIK3CAmut) in GBM are restricted to three functional domains: adaptor binding (ABD), helical, and kinase. Defining how these mutations influence gliomagenesis and response to kinase inhibitors may aid in the clinical development of novel targeted therapies in biomarker-stratified patients.
methodsWe used normal human astrocytes immortalized via expression of hTERT, E6, and E7 (NHA). We selected two PIK3CAmut from each of 3 mutated domains and induced their expression in NHA with (NHARAS) and without mutant RAS using lentiviral vectors. We then examined the role of PIK3CAmut in gliomagenesis in vitro and in mice, as well as response to targeted PI3K (PI3Ki) and MEK (MEKi) inhibitors in vitro.
resultsPIK3CAmut, particularly helical and kinase domain mutations, potentiated proximal PI3K signaling and migration of NHA and NHARAS in vitro. Only kinase domain mutations promoted NHA colony formation, but both helical and kinase domain mutations promoted NHARAS tumorigenesis in vivo. PIK3CAmut status had minimal effects on PI3Ki and MEKi efficacy. However, PI3Ki/MEKi synergism was pronounced in NHA and NHARAS harboring ABD or helical mutations.
conclusionPIK3CAmut promoted differential gliomagenesis based on the mutated domain. While PIK3CAmut did not influence sensitivity to single agent PI3Ki, they did alter PI3Ki/MEKi synergism. Taken together, our results demonstrate that a subset of PIK3CAmut promote tumorigenesis and suggest that patients with helical domain mutations may be most sensitive to dual PI3Ki/MEKi treatment.
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