Max Planck Institute for Neurological Research, Klaus-Joachim-Zülch Laboratories of the Max Planck Society, Köln, Germany.
Clin Cancer Res. 2011 Dec 1;17(23):7394-401. doi: 10.1158/1078-0432.CCR-11-1648. Epub 2011 Sep 26.
EML4-ALK fusions define a subset of lung cancers that can be effectively treated with anaplastic lymphoma kinase (ALK) inhibitors. Unfortunately, the duration of response is heterogeneous and acquired resistance limits their ultimate efficacy. Thus, a better understanding of resistance mechanisms will help to enhance tumor control in EML4-ALK-positive tumors.
By applying orthogonal functional mutagenesis screening approaches, we screened for mutations inducing resistance to the aminopyridine PF02341066 (crizotinib) and/or the diaminopyrimidine TAE684.
Here, we show that the resistance mutation, L1196M, as well as other crizotinib resistance mutations (F1174L and G1269S), are highly sensitive to the structurally unrelated ALK inhibitor TAE684. In addition, we identified two novel EML4-ALK resistance mutations (L1198P and D1203N), which unlike previously reported mutations, induced resistance to both ALK inhibitors. An independent resistance screen in ALK-mutant neuroblastoma cells yielded the same L1198P resistance mutation but defined two additional mutations conferring resistance to TAE684 but not to PF02341066.
Our results show that different ALK resistance mutations as well as different ALK inhibitors impact the therapeutic efficacy in the setting of EML4-ALK fusions and ALK mutations.
EML4-ALK 融合定义了可以有效治疗间变性淋巴瘤激酶（ALK）抑制剂的肺癌亚群。不幸的是，反应的持续时间是异质的，获得性耐药限制了它们的最终疗效。因此，更好地了解耐药机制将有助于提高 EML4-ALK 阳性肿瘤的肿瘤控制。
通过应用正交功能诱变筛选方法，我们筛选了导致对氨基吡啶 PF02341066（克唑替尼）和/或二氨基嘧啶 TAE684 耐药的突变。
在这里，我们表明耐药突变 L1196M 以及其他克唑替尼耐药突变（F1174L 和 G1269S）对结构上无关的 ALK 抑制剂 TAE684 高度敏感。此外，我们鉴定了两种新的 EML4-ALK 耐药突变（L1198P 和 D1203N），与先前报道的突变不同，这两种突变诱导对两种 ALK 抑制剂的耐药性。在 ALK 突变神经母细胞瘤细胞中的独立耐药筛选产生了相同的 L1198P 耐药突变，但定义了另外两种突变，这些突变对 TAE684 耐药，但对 PF02341066 不耐药。
我们的结果表明，不同的 ALK 耐药突变以及不同的 ALK 抑制剂在 EML4-ALK 融合和 ALK 突变的情况下影响治疗效果。
