Format

Send to

Choose Destination
Cancer Discov. 2013 Sep;3(9):1058-71. doi: 10.1158/2159-8290.CD-12-0569. Epub 2013 Jun 6.

Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3-mutant cancer.

Author information

1
1The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research; 2Breast Unit, Royal Marsden Hospital, London; 3Institute of Cancer Therapeutics, University of Bradford, Bradford; and 4Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, United Kingdom.

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.

PMID:
23744832
PMCID:
PMC3770512
DOI:
10.1158/2159-8290.CD-12-0569
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center