You are currently viewing the abstract.
View Full TextLog in to view the full text
AAAS login provides access to Science for AAAS members, and access to other journals in the Science family to users who have purchased individual subscriptions.
Register for free to read this article
As a service to the community, this article is available for free. Existing users log in.
More options
Download and print this article for your personal scholarly, research, and educational use.
Buy a single issue of Science for just $15 USD.
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.
Footnotes
-
↵* These authors contributed equally to this work.
-
↵† Present address: Cancer Research Technology, Gower Street, London WC1E 6BT, UK.
-
↵‡ Present address: Sanofi-Aventis, 13 Quai Jules Guesde, 94403 Vitry-sur-Seine, France.
-
↵§ Present address: Sanofi-Aventis, Cambridge, MA 02139, USA.
-
Citation: S. Buonamici, J. Williams, M. Morrissey, A. Wang, R. Guo, A. Vattay, K. Hsiao, J. Yuan, J. Green, B. Ospina, Q. Yu, L. Ostrom, P. Fordjour, D. L. Anderson, J. E. Monahan, J. F. Kelleher, S. Peukert, S. Pan, X. Wu, S.-M. Maira, C. García-Echeverría, K. J. Briggs, D. N. Watkins, Y.-m. Yao, C. Lengauer, M. Warmuth, W. R. Sellers, M. Dorsch, Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci. Transl. Med. 2, 51ra70 (2010).
- Copyright © 2010, American Association for the Advancement of Science