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.
Cancer Discov. 2013 Sep;3(9):1058-71. doi: 10.1158/2159-8290.CD-12-0569. Epub 2013 Jun 6.
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.
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.
成纤维细胞生长因子受体（FGFR）的激活是一种常见的致癌事件。对于 FGFR 抑制的敏感性决定因素以及这些因素如何在不同致癌性 FGFR 之间变化，人们知之甚少。我们使用平行 RNA 干扰（RNAi）遗传筛选，表明表皮生长因子受体（EGFR）限制了 FGFR3 突变和易位细胞系对 FGFR 抑制的敏感性，但对其他 FGFR 驱动的细胞系则不然。我们还确定了 EGFR 限制敏感性的两种不同机制。在部分 FGFR3 依赖性的细胞系中，FGFR3 的抑制导致丝裂原活化蛋白激酶信号的短暂下调，这可以通过 EGFR 信号的快速上调来挽救。在对 FGFR 抑制固有耐药的细胞系中，EGFR 通过抑制 FGFR3 来主导信号，通过延迟上调 FGFR3 表达来挽救 EGFR 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 RNAi 筛选在确定针对靶向治疗的常见耐药机制方面的强大功能。
我们的数据为治疗 FGFR3 突变型癌症提供了一种新的治疗方法，强调了针对 FGFR3 和 EGFR 的联合治疗方法的潜力。我们的数据扩展了 EGFR 在介导对靶向突变致癌基因的抑制剂的耐药性方面的作用，表明 EGFR 信号可以抑制突变的 FGFR3 以诱导对 FGFR 靶向的内在耐药性。
