Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities.
In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN). However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma. We demonstrate that the SHH and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and SHH signaling inhibitors not only suppressed the activation of both pathways but also abrogated S6 kinase (S6K) signaling. Accordingly, targeting both pathways simultaneously resulted in mitotic catastrophe and tumor apoptosis and markedly reduced the growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear to be safe in humans; therefore, this combination may provide a new targeted treatment for glioblastoma.
1] Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. [4] Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Mariella Gruber
MG
Filbin
Sukriti K
SK
Dabral
Maria F
MF
Pazyra-Murphy
Shakti
S
Ramkissoon
Andrew L
AL
Kung
Ekaterina
E
Pak
Jarom
J
Chung
Matthew A
MA
Theisen
Yanping
Y
Sun
Yoko
Y
Franchetti
Yu
Y
Sun
David S
DS
Shulman
Navid
N
Redjal
Barbara
B
Tabak
Rameen
R
Beroukhim
Qi
Q
Wang
Jean
J
Zhao
Marion
M
Dorsch
Silvia
S
Buonamici
Keith L
KL
Ligon
Joseph F
JF
Kelleher
Rosalind A
RA
Segal
D000631:Aminopyridines / Q000008:administration & dosage; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000008:administration & dosage; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000008:administration & dosage; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000631:Aminopyridines; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D053823:Hedgehog Proteins; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D019893:Ribosomal Protein S6 Kinases; C571178:NVP-BKM120; C509239:SHH protein, human; C561435:sonidegib; C494929:PTEN protein, human