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| Status |
Public on Mar 13, 2012 |
| Title |
Effect of a dual specificity PI3K/mTOR inhibitor, NVP-BEZ235, on human ovarian cancer cell lines grown in 3D culture |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Analysis of the effects of a dual specificity PI3K/mTOR inhibitor on two human ovarian cell lines, OV2008 and MCAS. Results provide insight into the adaptive response to PI3K/mTOR inhibition in matrix attached ovarian cancer cells.
The PI3K/mTOR-pathway is the most commonly deregulated pathway in epithelial cancers and thus represents an important target for cancer therapeutics. Here we show that dual inhibition of PI3K/mTOR in ovarian cancer 3D-spheroids leads to death of the inner matrix-deprived cells, whereas matrix-attached cells are resistant. Resistance is associated with up-regulation of a cellular survival program that involves both FOXO-regulated transcription and a novel translational resistance mechanism resulting in specific up-regulation of IRES-mediated, cap-independent translation. Inhibition of any of several up-regulated proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to dual PI3K/mTOR inhibition. These results demonstrate that acute adaptive response to PI3K/mTOR inhibition resembles well-conserved adaptive response to nutrient and growth factor deprivation and how development of rational drug combinations can bypass resistance mechanisms.
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| Overall design |
Total RNA was isolated 6h and 24h after treatment with 1 μM NVP-BEZ235 or DMSO vehicle control from 3D grown structures
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| Contributor(s) |
Muranen T, Selfors LM, Morales FC, Mills GB, Brugge JS |
| Citation(s) |
22340595 |
| Submission date |
Apr 29, 2011 |
| Last update date |
Aug 13, 2018 |
| Contact name |
Joan S. Brugge |
| E-mail(s) |
joan_brugge@hms.harvard.edu
|
| Organization name |
Harvard Medical School
|
| Department |
Department of Cell Biology
|
| Lab |
Brugge
|
| Street address |
240 Longwood Avenue
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA140511 |
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