Title |
A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer
|
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Published in |
Nature Chemical Biology, September 2011
|
DOI | 10.1038/nchembio.695 |
Pubmed ID | |
Authors |
Markus K Muellner, Iris Z Uras, Bianca V Gapp, Claudia Kerzendorfer, Michal Smida, Hannelore Lechtermann, Nils Craig-Mueller, Jacques Colinge, Gerhard Duernberger, Sebastian M B Nijman |
Abstract |
Linking the molecular aberrations of cancer to drug responses could guide treatment choice and identify new therapeutic applications. However, there has been no systematic approach for analyzing gene-drug interactions in human cells. Here we establish a multiplexed assay to study the cellular fitness of a panel of engineered isogenic cancer cells in response to a collection of drugs, enabling the systematic analysis of thousands of gene-drug interactions. Applying this approach to breast cancer revealed various synthetic-lethal interactions and drug-resistance mechanisms, some of which were known, thereby validating the method. NOTCH pathway activation, which occurs frequently in breast cancer, unexpectedly conferred resistance to phosphoinositide 3-kinase (PI3K) inhibitors, which are currently undergoing clinical trials in breast cancer patients. NOTCH1 and downstream induction of c-MYC over-rode the dependency of cells on the PI3K-mTOR pathway for proliferation. These data reveal a new mechanism of resistance to PI3K inhibitors with direct clinical implications. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Austria | 1 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Germany | 3 | 2% |
Austria | 2 | 1% |
United Kingdom | 2 | 1% |
Italy | 1 | <1% |
Sweden | 1 | <1% |
Australia | 1 | <1% |
Japan | 1 | <1% |
United States | 1 | <1% |
Unknown | 148 | 93% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 44 | 28% |
Student > Ph. D. Student | 29 | 18% |
Professor > Associate Professor | 12 | 8% |
Student > Master | 12 | 8% |
Other | 9 | 6% |
Other | 29 | 18% |
Unknown | 25 | 16% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 59 | 37% |
Biochemistry, Genetics and Molecular Biology | 29 | 18% |
Medicine and Dentistry | 23 | 14% |
Chemistry | 17 | 11% |
Pharmacology, Toxicology and Pharmaceutical Science | 4 | 3% |
Other | 3 | 2% |
Unknown | 25 | 16% |