Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma.
The malignant brain cancer medulloblastoma is characterized by mutations in Hedgehog (Hh) signaling pathway genes, which lead to constitutive activation of the G protein (heterotrimeric guanosine triphosphate-binding protein)-coupled receptor Smoothened (Smo). The Smo antagonist NVP-LDE225 inhibits Hh signaling and induces tumor regression in animal models of medulloblastoma. However, evidence of resistance was observed during the course of treatment. Molecular analysis of resistant tumors revealed several resistance mechanisms. We noted chromosomal amplification of Gli2, a downstream effector of Hh signaling, and, more rarely, point mutations in Smo that led to reactivated Hh signaling and restored tumor growth. Analysis of pathway gene expression signatures also, unexpectedly, identified up-regulation of phosphatidylinositol 3-kinase (PI3K) signaling in resistant tumors as another potential mechanism of resistance. Probing the relevance of increased PI3K signaling, we demonstrated that addition of the PI3K inhibitor NVP-BKM120 or the dual PI3K-mTOR (mammalian target of rapamycin) inhibitor NVP-BEZ235 to the initial treatment with the Smo antagonist markedly delayed the development of resistance. Our findings may be useful in informing treatment strategies for medulloblastoma.
Buonamici
Silvia
S
Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
Williams
Juliet
J
Morrissey
Michael
M
Wang
Anlai
A
Guo
Ribo
R
Vattay
Anthony
A
Hsiao
Kathy
K
Yuan
Jing
J
Green
John
J
Ospina
Beatriz
B
Yu
Qunyan
Q
Ostrom
Lance
L
Fordjour
Paul
P
Anderson
Dustin L
DL
Monahan
John E
JE
Kelleher
Joseph F
JF
Peukert
Stefan
S
Pan
Shifeng
S
Wu
Xu
X
Maira
Sauveur-Michel
SM
García-Echeverría
Carlos
C
Briggs
Kimberly J
KJ
Watkins
D Neil
DN
Yao
Yung-mae
YM
Lengauer
Christoph
C
Warmuth
Markus
M
Sellers
William R
WR
Dorsch
Marion
M
D000631:Aminopyridines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005784:Gene Amplification / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008527:Medulloblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000075746:Zinc Finger Protein Gli2
D000631:Aminopyridines; D053823:Hedgehog Proteins; D007334:Insulin-Like Growth Factor I; D051741:Kruppel-Like Transcription Factors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; D016159:Tumor Suppressor Protein p53; D000075746:Zinc Finger Protein Gli2; C000618551:Gli2 protein, mouse; C571178:NVP-BKM120; C491022:Smo protein, mouse