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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Sep 29, 2010 |
| Title |
Targeting resistance to Smoothened antagonists by inhibiting the PI3K pathway |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
Genome variation profiling by genome tiling array
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| Summary |
Mutations in Hedgehog (Hh) pathway genes, leading to constitutive activation of Smoothened (Smo), occur in sporadic medulloblastoma, the most common brain cancer in children. Antagonists of Smo induce tumor regression in mouse models of medulloblastoma and hold great promise for targeted therapy for this tumor. However, acquired resistance has emerged as one of the major challenges of targeted cancer therapy. Here, we describe novel mechanisms of acquired resistance to Smo antagonists in medulloblastoma. NVP-LDE225, a potent and selective Smo antagonist, inhibits Hh signaling and induces tumor regressions in allograft models of medulloblastoma that are driven by mutations of Patched (Ptch), a tumor suppressor in the Hh pathway. However, after long-term treatment, evidence of acquired resistance was observed. Genome-wide profiling of resistant tumors revealed distinct mechanisms to evade the inhibitory effects of Smo antagonists. Chromosomal amplification of Gli2, a downstream effector of Hh signaling, reactivated Hh signaling and restored tumor growth. Analysis of pathway gene-expression signatures selectively deregulated in resistant tumors identified increased phosphoinosite-3-kinase (PI3K) signaling as another potential resistance mechanism. Probing the functional relevance of increased PI3K signaling, we showed that the combination of NVP-LDE225 with the dual PI3K/mTOR inhibitor NVP-BEZ235 markedly delayed the development of resistance. Our findings have important clinical implications for future treatment strategies in medulloblastoma.
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| Overall design |
mRNA profiling: RNA was prepared from tumours from vehicle or NVP-LDE225 treated nude mice allografted with medulloblastoma tumors derived from Ptch+/-p53-/- transgenic mouse and hybridized on Affymetrix Mouse Genome 430 2.0 RNA expression array. The dosage terminology (BID & QD) reflects the dosing schedule, where BID = twice a day, QD = once a day.
aCGH: DNA was prepared from tumors from vehicle or NVP-LDE225 treated nude mice allografted with medulloblastoma tumors derived from Ptch+/-p53-/- transgenic mouse and hybridized on Agilent mouse CGH 244K Array.
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| Contributor(s) |
Buonamici S, Monahan JE |
| Citation(s) |
20881279 |
| Submission date |
Dec 24, 2009 |
| Last update date |
Feb 11, 2019 |
| Contact name |
John E Monahan |
| E-mail(s) |
john.monahan@novartis.com
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| Phone |
617-871-7319
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| Organization name |
Novartis
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| Department |
Oncology Translational Research
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| Street address |
250 Massachusetts Ave
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02139 |
| Country |
USA |
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| Platforms (2) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
| GPL4092 |
Agilent-014695 Mouse Genome CGH Microarray 244A (G4415A) (Feature Number version) |
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| Samples (27)
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| GSM490286 |
Veh-16h, Mouse 1 (mRNA) |
| GSM490287 |
Veh-16h, Mouse 2 (mRNA) |
| GSM490288 |
Veh-16h, Mouse 3 (mRNA) |
| GSM490289 |
Veh-48h, Mouse 1 (mRNA) |
| GSM490290 |
Veh-48h, Mouse 3 (mRNA) |
| GSM490291 |
LDE-4h 20 mg/kg/day qd, Mouse 1 (mRNA) |
| GSM490292 |
LDE-4h 20 mg/kg/day qd, Mouse 2 (mRNA) |
| GSM490293 |
LDE-4h 20 mg/kg/day qd, Mouse 3 (mRNA) |
| GSM490294 |
LDE-16h 20 mg/kg/day qd, Mouse 1 (mRNA) |
| GSM490295 |
LDE-16h 20 mg/kg/day qd, Mouse 2 (mRNA) |
| GSM490296 |
LDE-16h 20 mg/kg/day qd, Mouse 3 (mRNA) |
| GSM490297 |
LDE-48h 20 mg/kg/day qd, Mouse 1 (mRNA) |
| GSM490298 |
LDE-48h 20 mg/kg/day qd, Mouse 2 (mRNA) |
| GSM490299 |
LDE RES 20 mg/kg/day bid, Mouse 1 (mRNA) |
| GSM490300 |
LDE RES 20 mg/kg/day bid, Mouse 2 (mRNA) |
| GSM490301 |
LDE RES 160 mg/kg/day bid, Mouse 1 (mRNA) |
| GSM490302 |
LDE RES 160 mg/kg/day bid, Mouse 2 (mRNA) |
| GSM490303 |
LDE RES 160 mg/kg/day bid, Mouse 3 (mRNA) |
| GSM490321 |
Ptch+/-p53-/- tumors, vehicle treated for 26 days, 1 (aCGH) |
| GSM490322 |
Ptch+/-p53-/- tumors, vehicle treated for 26 days, 2 (aCGH) |
| GSM490323 |
Ptch+/-p53-/- tumors, vehicle treated for 26 days, 3 (aCGH) |
| GSM490324 |
Ptch+/-p53-/- tumors, LDE225 treated for 26 days, 40 mg/kg/day bid (aCGH) |
| GSM490325 |
Ptch+/-p53-/- tumors, LDE225 treated for 26 days, 80 mg/kg/day bid (aCGH) |
| GSM490326 |
Ptch+/-p53-/- tumors, vehicle treated for 26 days, 160 mg/kg/day bid (aCGH) |
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| Relations |
| BioProject |
PRJNA122559 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE19657_RAW.tar |
499.5 Mb |
(http)(custom) |
TAR (of CEL, TXT) |
| Processed data included within Sample table |
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