Title |
Parallel RNA Interference Screens Identify EGFR Activation as an Escape Mechanism in FGFR3-Mutant Cancer
|
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Published in |
Cancer Discovery, September 2013
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DOI | 10.1158/2159-8290.cd-12-0569 |
Pubmed ID | |
Authors |
Maria Teresa Herrera-Abreu, Alex Pearson, James Campbell, Steve D. Shnyder, Margaret A. Knowles, Alan Ashworth, Nicholas C. Turner |
Abstract |
Activation of fibroblast growth factor receptors (FGFR) is a common oncogenic event. Little is known about the determinants of sensitivity to FGFR inhibition and how these may vary between different oncogenic FGFRs. Using parallel RNA interference (RNAi) genetic screens, we show that the EGF receptor (EGFR) limits sensitivity to FGFR inhibition in FGFR3-mutant and -translocated cell lines, but not in other FGFR-driven cell lines. We also identify two distinct mechanisms through which EGFR limits sensitivity. In partially FGFR3-dependent lines, inhibition of FGFR3 results in transient downregulation of mitogen-activated protein kinase signaling that is rescued by rapid upregulation of EGFR signaling. In cell lines that are intrinsically resistant to FGFR inhibition, EGFR dominates signaling via repression of FGFR3, with EGFR inhibition rescued by delayed upregulation of FGFR3 expression. Importantly, combinations of FGFR and EGFR inhibitors overcome these resistance mechanisms in vitro and in vivo. Our results illustrate the power of parallel RNAi screens in identifying common resistance mechanisms to targeted therapies. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 1 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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United States | 2 | 2% |
Austria | 1 | 1% |
Unknown | 92 | 97% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 29 | 31% |
Student > Ph. D. Student | 16 | 17% |
Student > Master | 10 | 11% |
Other | 7 | 7% |
Student > Bachelor | 6 | 6% |
Other | 15 | 16% |
Unknown | 12 | 13% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 31 | 33% |
Agricultural and Biological Sciences | 24 | 25% |
Medicine and Dentistry | 22 | 23% |
Computer Science | 1 | 1% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 1% |
Other | 2 | 2% |
Unknown | 14 | 15% |