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

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.