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

Autor: McNeill RS; Pathobiology and Translational Science Graduate Program, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America., Stroobant EE; Department of Chemistry, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America., Smithberger E; Pathobiology and Translational Science Graduate Program, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America., Canoutas DA; Department of Biology, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America., Butler MK; Department of Biology, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America., Shelton AK; Pathobiology and Translational Science Graduate Program, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America., Patel SD; Department of Chemistry, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America., Limas JC; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America., Skinner KR; Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America., Bash RE; Departments of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America., Schmid RS; Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America.; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America., Miller CR; Pathobiology and Translational Science Graduate Program, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America.; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America.; Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America.; Departments of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America.; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America.; Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2018 Jul 05; Vol. 13 (7), pp. e0200014. Date of Electronic Publication: 2018 Jul 05 (Print Publication: 2018).
DOI: 10.1371/journal.pone.0200014
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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