Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3 mutant cancer
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels l'activation du gène EGFR favorise la résistance thérapeutique aux inhibiteurs de FGFR dans les tumeurs présentant une mutation du gène FGFR3
Activation of fibroblast growth factor receptors 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 genetic screens we demonstrate that 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 down-regulation of MAPK signalling that is rescued by rapid upregulation of EGFR signalling. In cell lines that are intrinsically resistant to FGFR inhibition, EGFR dominates signalling via repression of FGFR3, with EGFR inhibition rescued by delayed up-regulation 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 RNA interference screens in identifying common resistance mechanisms to targeted therapies.