Herrera-Abreu, MT, Pearson, A, Campbell, J et al. (4 more authors) (2013) Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3-mutant cancer. Cancer Discovery, 3 (9). 1058 - 1071. ISSN 2159-8274
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. SIGNIFICANCE: Our data identify a novel therapeutic approach to the treatment of FGFR3-mutant cancer, emphasizing the potential of combination approaches targeting both FGFR3 and EGFR. Our data extend the role of EGFR in mediating resistance to inhibitors targeting a mutant oncogene, showing that EGFR signaling can repress mutant FGFR3 to induce intrinsic resistance to FGFR targeting.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2013 American Association for Cancer Research. This is an author produced version of a paper published in Cancer Discovery. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Animals; Cell Line, Tumor; Heterografts; High-Throughput Screening Assays; Humans; MAP Kinase Signaling System; Mice; Neoplasm Transplantation; Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Quinazolines; RNA Interference; RNA, Small Interfering; Receptor, Epidermal Growth Factor; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction; Thiazoles |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Experimental Oncology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Section of Experimental Oncology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 09 Nov 2015 16:52 |
Last Modified: | 03 Nov 2017 04:16 |
Published Version: | http://dx.doi.org/10.1158/2159-8290.CD-12-0569 |
Status: | Published |
Publisher: | American Association for Cancer Research |
Identification Number: | 10.1158/2159-8290.CD-12-0569 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:86570 |