title: Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma.
abstract: 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.
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Buonamici
authors.forename: Juliet
authors.initials: J
authors.lastname: Williams
authors.forename: Michael
authors.initials: M
authors.lastname: Morrissey
authors.forename: Anlai
authors.initials: A
authors.lastname: Wang
authors.forename: Ribo
authors.initials: R
authors.lastname: Guo
authors.forename: Anthony
authors.initials: A
authors.lastname: Vattay
authors.forename: Kathy
authors.initials: K
authors.lastname: Hsiao
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.forename: John
authors.initials: J
authors.lastname: Green
authors.forename: Beatriz
authors.initials: B
authors.lastname: Ospina
authors.forename: Qunyan
authors.initials: Q
authors.lastname: Yu
authors.forename: Lance
authors.initials: L
authors.lastname: Ostrom
authors.forename: Paul
authors.initials: P
authors.lastname: Fordjour
authors.forename: Dustin L
authors.initials: DL
authors.lastname: Anderson
authors.forename: John E
authors.initials: JE
authors.lastname: Monahan
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Kelleher
authors.forename: Stefan
authors.initials: S
authors.lastname: Peukert
authors.forename: Shifeng
authors.initials: S
authors.lastname: Pan
authors.forename: Xu
authors.initials: X
authors.lastname: Wu
authors.forename: Sauveur-Michel
authors.initials: SM
authors.lastname: Maira
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Echeverría
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Briggs
authors.forename: D Neil
authors.initials: DN
authors.lastname: Watkins
authors.forename: Yung-mae
authors.initials: YM
authors.lastname: Yao
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
authors.forename: Markus
authors.initials: M
authors.lastname: Warmuth
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
mesh_terms: 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
chemical_list: 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