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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Glioblastoma (GBM) is the most common primary brain tumor in adults, characterized by poor prognosis and empirical treatment strategies.
• Recurrent PIK3CA missense mutations (PIK3CAmut) in GBM are specifically located in the adaptor binding (ABD), helical, and kinase domains.
• Understanding the impact of these mutations on gliomagenesis and response to kinase inhibitors is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the role of PIK3CA mutations in different functional domains on gliomagenesis.
• To evaluate the response of cells with PIK3CA mutations to PI3K inhibitors (PI3Ki) and MEK inhibitors (MEKi).
• To identify potential therapeutic strategies for biomarker-stratified GBM patients.

Main Methods:

• Utilized immortalized normal human astrocytes (NHA) engineered to express specific PIK3CA mutations from ABD, helical, and kinase domains.
• Assessed gliomagenesis in vitro and in vivo (mice) in NHA with and without mutant RAS (NHARAS).
• Examined the in vitro efficacy of PI3Ki and MEKi, and their synergistic effects.

Main Results:

• PIK3CAmut, especially in helical and kinase domains, enhanced PI3K signaling and migration in vitro.
• Kinase domain mutations promoted NHA colony formation, while helical and kinase mutations drove NHARAS tumorigenesis in vivo.
• PIK3CAmut had minor effects on single-agent PI3Ki and MEKi efficacy, but synergism was notable with PI3Ki/MEKi in cells with ABD or helical mutations.

Conclusions:

• PIK3CA mutations differentially influence gliomagenesis depending on the affected domain.
• While PIK3CAmut did not alter sensitivity to single PI3Ki, they modulated PI3Ki/MEKi synergism.
• Patients with helical domain PIK3CA mutations may benefit most from combined PI3Ki and MEKi therapy.