Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute The University of Manchester, Manchester, UK.
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute The University of Manchester, Manchester, UK.
EMBO Mol Med. 2016 Feb 1;8(2):105-16. doi: 10.15252/emmm.201505456.
The lack of actionable mutations in patients with non-small cell lung cancer (NSCLC) presents a significant hurdle in the design of targeted therapies for this disease. Here, we identify somatically mutated ABL1 as a genetic dependency that is required to maintain NSCLC cell survival. We demonstrate that NSCLC cells with ABL1 mutations are sensitive to ABL inhibitors and we verify that the drug-induced effects on cell viability are specific to pharmacological inhibition of the ABL1 kinase. Furthermore, we confirm that imatinib suppresses lung tumor growth in vivo, specifically in lung cancer cells harboring a gain-of-function (GOF) mutation in ABL1. Consistent with structural modeling, we demonstrate that mutations in ABL1 identified in primary NSCLC tumors and a lung cancer cell line increase downstream pathway activation compared to wild-type ABL1. Finally, we observe that the ABL1 cancer mutants display an increased cytosolic localization, which is associated with the oncogenic properties of the ABL1 kinase. In summary, our results suggest that NSCLC patients with ABL1 mutations could be stratified for treatment with imatinib in combination with other therapies.
非小细胞肺癌（NSCLC）患者缺乏可操作的突变，这给针对这种疾病的靶向治疗设计带来了重大障碍。在这里，我们确定体细胞突变的 ABL1 是维持 NSCLC 细胞存活所必需的遗传依赖性。我们证明了具有 ABL1 突变的 NSCLC 细胞对 ABL 抑制剂敏感，并且我们验证了药物对细胞活力的影响是针对 ABL1 激酶的药理学抑制特异性的。此外，我们证实伊马替尼在体内抑制肺肿瘤生长，特别是在携带 ABL1 获得性功能（GOF）突变的肺癌细胞中。与结构建模一致，我们证明与野生型 ABL1 相比，在原发性 NSCLC 肿瘤和肺癌细胞系中鉴定的 ABL1 突变增加了下游途径的激活。最后，我们观察到 ABL1 癌症突变体显示出增加的细胞质定位，这与 ABL1 激酶的致癌特性有关。总之，我们的研究结果表明，具有 ABL1 突变的 NSCLC 患者可以用伊马替尼与其他疗法联合进行分层治疗。
