AI Article Synopsis
- Glioblastoma (GBM) is a common and aggressive brain tumor with poor prognosis, and specific mutations in the PIK3CA gene are believed to play a crucial role in tumor growth and reaction to treatment.
- Researchers examined the effects of PIK3CA mutations in both normal human astrocytes and mouse models to understand their role in gliomagenesis and treatment response using targeted inhibitors.
- Findings showed that specific mutations in the PIK3CA gene influence tumor formation differently; while they didn't affect sensitivity to single inhibitors, mutations in the helical domain enhanced the effectiveness of combined PI3K and MEK inhibitors, suggesting a potential targeted therapy approach for patients with these mutations.
Article Abstract
Background: Glioblastoma (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.
Methods: We 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.
Results: PIK3CAmut, 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.
Conclusion: PIK3CAmut 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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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033446 | PMC |
| http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200014 | PLOS |
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