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20881279
Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma.

Sci Transl Med, 2010/9/29;2(51):51ra70.

Buonamici S[1], Williams J, Morrissey M, Wang A, Guo R, Vattay A, Hsiao K, Yuan J, Green J, Ospina B, Yu Q, Ostrom L, Fordjour P, Anderson DL, Monahan JE, Kelleher JF, Peukert S, Pan S, Wu X, Maira SM, García-Echeverría C, Briggs KJ, Watkins DN, Yao YM, Lengauer C, Warmuth M, Sellers WR, Dorsch M

Affiliations

PMID: 20881279DOI: 10.1126/scitranslmed.3001599

Impact factor: 19.319

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.
MeSH terms
Aminopyridines; Animals; Cell Proliferation; Drug Resistance, Neoplasm; Gene Amplification; Hedgehog Proteins; Insulin-Like Growth Factor I; Kruppel-Like Transcription Factors; Medulloblastoma; Mice; Morpholines; Mutation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Receptors, G-Protein-Coupled; Signal Transduction; Smoothened Receptor; Tumor Suppressor Protein p53; Up-Regulation; Zinc Finger Protein Gli2
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