Reference Detail

Ref Type

Journal Article

PMID

(29975751)

Authors

McNeill RS, Stroobant EE, Smithberger E, Canoutas DA, Butler MK, Shelton AK, Patel SD, Limas JC, Skinner KR, Bash RE, Schmid RS, Miller CR

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
PloS one	13	7	2018	e0200014	PLoS One

URL

Abstract Text

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.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.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.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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
HRAS mut PIK3CA R88Q	high grade glioma	sensitive	Buparlisib + Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination therapy of Buparlisib (BKM120) and Koselugo (selumetinib) led to a synergistic effect, resulting in growth inhibition of astrocytoma cells with an HRAS mutation and expressing PIK3CA R88Q in culture, but at a higher drug concentration compared to cells without mutant HRAS (PMID: 29975751).	29975751
HRAS mut PIK3CA M1043V	high grade glioma	sensitive	Buparlisib + Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination therapy of Buparlisib (BKM120) and Koselugo (selumetinib) led to a synergistic effect, resulting in growth inhibition of astrocytoma cells with an HRAS mutation and expressing PIK3CA M1043V in culture, but at a higher drug concentration compared to cells without mutant HRAS (PMID: 29975751).	29975751
PIK3CA H1047R	high grade glioma	sensitive	Buparlisib + Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination therapy of Buparlisib (BKM120) and Koselugo (selumetinib) led to a synergistic effect, resulting in growth inhibition of astrocytoma cells expressing PIK3CA H1047R, but did not result in an effect as high as that seen in cells expressing PIK3CA R88Q or PIK3CA E542K in culture (PMID: 29975751).	29975751
PIK3CA E542K	high grade glioma	sensitive	Buparlisib + Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination therapy of Buparlisib (BKM120) and Koselugo (selumetinib) led to a synergistic effect, resulting in greater growth inhibition of astrocytoma cells expressing PIK3CA E542K than cells with wild-type PIK3CA in culture (PMID: 29975751).	29975751
HRAS mut PIK3CA E542K	high grade glioma	sensitive	Buparlisib + Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination therapy of Buparlisib (BKM120) and Koselugo (selumetinib) led to a synergistic effect, resulting in growth inhibition of astrocytoma cells with an HRAS mutation expressing PIK3CA E542K in culture, but at a higher drug concentration compared to cells without mutant HRAS (PMID: 29975751).	29975751
PIK3CA R88Q	high grade glioma	sensitive	Buparlisib + Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination therapy of Buparlisib (BKM120) and Koselugo (selumetinib) led to a synergistic effect, resulting in greater growth inhibition of astrocytoma cells expressing PIK3CA R88Q than cells with wild-type PIK3CA in culture (PMID: 29975751).	29975751