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

Silvia Buonamici, Juliet Williams, Michael Morrissey, Anlai Wang, Ribo Guo, Anthony Vattay, Kathy Hsiao, Jing Yuan, John Green, Beatriz Ospina, Qunyan Yu, Lance Ostrom, Paul Fordjour, Dustin L. Anderson, John E. Monahan, Joseph F. Kelleher, Stefan Peukert, Shifeng Pan, Xu Wu, Sauveur Michel MairaCarlos García-Echeverría, Kimberly J. Briggs, D. Neil Watkins, Yung Mae Yao, Christoph Lengauer, Markus Warmuth, William R. Sellers, Marion Dorsch

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number51ra70
JournalScience Translational Medicine
Volume2
Issue number51
DOIs
StatePublished - Sep 29 2010
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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