Interfering with Resistance to Smoothened Antagonists by Inhibition of the PI3K Pathway in Medulloblastoma

被引：393

作者：

Buonamici, Silvia ^{[1
]}

Williams, Juliet ^{[1
]}

Morrissey, Michael ^{[1
]}

Wang, Anlai ^{[1
]}

Guo, Ribo ^{[1
]}

Vattay, Anthony ^{[1
]}

Hsiao, Kathy ^{[1
]}

Yuan, Jing ^{[1
]}

Green, John ^{[1
]}

Ospina, Beatriz ^{[1
]}

Yu, Qunyan ^{[1
]}

Ostrom, Lance ^{[1
]}

Fordjour, Paul ^{[1
]}

Anderson, Dustin L. ^{[1
]}

Monahan, John E. ^{[1
]}

Kelleher, Joseph F. ^{[1
]}

Peukert, Stefan ^{[1
]}

Pan, Shifeng ^{[2
]}

Wu, Xu ^{[2
]}

Maira, Sauveur-Michel ^{[3
]}

Garcia-Echeverria, Carlos ^{[3
]}

Briggs, Kimberly J. ^{[4
]}

Watkins, D. Neil ^{[5
]}

Yao, Yung-mae ^{[1
]}

Lengauer, Christoph ^{[1
]}

Warmuth, Markus ^{[1
]}

Sellers, William R. ^{[1
]}

Dorsch, Marion ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[2] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

[3] Novartis Inst Biomed Res, CH-4057 Basel, Switzerland

[4] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA

[5] Monash Univ, Monash Inst Med Res, Clayton, Vic 3168, Australia

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2010年 / 2卷 / 51期

关键词：

ANTITUMOR-ACTIVITY; SONIC-HEDGEHOG; GROWTH-FACTOR; MICE; PROGRESSION; CONVERGE; CANCER; POTENT;

D O I：

10.1126/scitranslmed.3001599

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：8

共 27 条

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