TY - JOUR
T1 - Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma
AU - Buonamici, Silvia
AU - Williams, Juliet
AU - Morrissey, Michael
AU - Wang, Anlai
AU - Guo, Ribo
AU - Vattay, Anthony
AU - Hsiao, Kathy
AU - Yuan, Jing
AU - Green, John
AU - Ospina, Beatriz
AU - Yu, Qunyan
AU - Ostrom, Lance
AU - Fordjour, Paul
AU - Anderson, Dustin L.
AU - Monahan, John E.
AU - Kelleher, Joseph F.
AU - Peukert, Stefan
AU - Pan, Shifeng
AU - Wu, Xu
AU - Maira, Sauveur Michel
AU - García-Echeverría, Carlos
AU - Briggs, Kimberly J.
AU - Watkins, D. Neil
AU - Yao, Yung Mae
AU - Lengauer, Christoph
AU - Warmuth, Markus
AU - Sellers, William R.
AU - Dorsch, Marion
PY - 2010/9/29
Y1 - 2010/9/29
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.3001599
DO - 10.1126/scitranslmed.3001599
M3 - Article
C2 - 20881279
AN - SCOPUS:77958060845
SN - 1946-6234
VL - 2
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 51
M1 - 51ra70
ER -