English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background  Glioblastoma (GBM) is the most common adult primary brain tumor. Multimodal treatment is empiric and prognosis remains poor. Recurrent  PIK3CA  missense mutations ( PIK3CA   mut  ) 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  PIK3CA   mut   from each of 3 mutated domains and induced their expression in NHA with (NHA RAS ) and without mutant  RAS  using lentiviral vectors. We then examined the role of  PIK3CA   mut   in gliomagenesis  in vitro  and in mice, as well as response to targeted PI3K (PI3Ki) and MEK (MEKi) inhibitors  in vitro .    Results   PIK3CA   mut  , particularly helical and kinase domain mutations, potentiated proximal PI3K signaling and migration of NHA and NHA RAS   in vitro . Only kinase domain mutations promoted NHA colony formation, but both helical and kinase domain mutations promoted NHA RAS  tumorigenesis  in vivo .  PIK3CA   mut   status had minimal effects on PI3Ki and MEKi efficacy. However, PI3Ki/MEKi synergism was pronounced in NHA and NHA RAS  harboring ABD or helical mutations.    Conclusion   PIK3CA   mut   promoted differential gliomagenesis based on the mutated domain. While  PIK3CA   mut   did not influence sensitivity to single agent PI3Ki, they did alter PI3Ki/MEKi synergism. Taken together, our results demonstrate that a subset of  PIK3CA   mut   promote tumorigenesis and suggest that patients with helical domain mutations may be most sensitive to dual PI3Ki/MEKi treatment.

PIK3CA missense mutations promote glioblastoma pathogenesis, but do not enhance targeted PI3K inhibition