Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3-mutant cancer.
Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3-mutant cancer.
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DOI：
10.1158/2159-8290.cd-12-0569
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发表时间：
2013-09
期刊：
影响因子：
28.2
通讯作者：
Turner NC
中科院分区：
文献类型：
--
作者：
Herrera-Abreu MT;Pearson A;Campbell J;Shnyder SD;Knowles MA;Ashworth A;Turner NC
成纤维细胞生长因子受体的激活是一种常见的致癌事件。对FGFR抑制敏感性的决定因素以及这些决定因素在不同致癌FGFR之间的差异还知之甚少。使用平行的RNA干扰遗传筛选，我们证明了在FGFR3突变和易位的细胞系中，EGFR限制了对FGFR抑制的敏感性，但在其他FGFR驱动的细胞系中不限制。我们还发现了两种不同的EGFR限制敏感性的机制。在部分依赖于FGFR3的细胞系中，抑制FGFR3会导致MAPK信号的瞬时下调，而这种下调可以通过快速上调EGFR信号来挽救。在对FGFR抑制具有内在抵抗力的细胞系中，EGFR通过抑制FGFR3来主导信号转导，而通过延迟上调FGFR3的表达来挽救EGFR的抑制。重要的是，FGFR和EGFR抑制剂的组合在体外和体内克服了这些耐药机制。我们的结果说明了平行RNA干扰筛选在识别靶向治疗的常见耐药机制方面的能力。
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.