Pilling Amanda B, Kim Jihye, Estrada-Bernal Adriana, Zhou Qiong, Le Anh T, Singleton Katherine R, Heasley Lynn E, Tan Aik Choon, DeGregori James, Doebele Robert C
University of Colorado Cancer Center, Aurora, CO, USA.
Henry Ford Cancer Institute, Detroit, MI, USA.
Oncotarget. 2018 Jan 16;9(10):8823-8835. doi: 10.18632/oncotarget.24260. eCollection 2018 Feb 6.
A subset of lung cancers is dependent on the anaplastic lymphoma kinase () oncogene for survival, a mechanism that is exploited by the use of the ALK inhibitor crizotinib. Despite exceptional initial tumor responses to ALK inhibition by crizotinib, durable clinical response is limited and the emergence of drug resistance occurs. Furthermore, intrinsic resistance is frequently observed, where patients fail to respond initially to ALK-inhibitor therapy. These events demonstrate the underlying complexity of a molecularly-defined oncogene-driven cancer and highlights the need to identify compensating survival pathways. Using a loss-of-function whole genome short-hairpin (shRNA) screen, we identified MYCBP as a determinant of response to crizotinib, implicating the MYC signaling axis in resistance to crizotinib-treated NSCLC. Further analysis reveals that ALK regulates transcriptional expression of and activates c-MYC transactivation of c-MYC target genes. Inhibition of by RNAi or small molecules sensitizes cells to crizotinib. Taken together, our findings demonstrate a dual oncogene mechanism, where ALK positively regulates the MYC signaling axis, providing an additional oncogene target whose inhibition may prevent or overcome resistance.
一部分肺癌依赖间变性淋巴瘤激酶（ALK）致癌基因来维持生存，这一机制可通过使用ALK抑制剂克唑替尼来加以利用。尽管克唑替尼对ALK的抑制作用最初能使肿瘤产生显著反应，但持久的临床反应有限，且会出现耐药性。此外，经常观察到内在耐药性，即患者最初对ALK抑制剂治疗无反应。这些情况表明了分子定义的致癌基因驱动癌症的潜在复杂性，并突出了识别代偿性生存途径的必要性。通过功能丧失性全基因组短发夹RNA（shRNA）筛选，我们确定MYCBP是对克唑替尼反应的一个决定因素，这表明MYC信号轴与克唑替尼治疗的非小细胞肺癌（NSCLC）的耐药性有关。进一步分析显示，ALK调节MYC的转录表达并激活c-MYC靶基因的c-MYC反式激活。通过RNA干扰或小分子抑制MYC可使细胞对克唑替尼敏感。综上所述，我们的研究结果证明了一种双重致癌基因机制，其中ALK正向调节MYC信号轴，提供了一个额外的致癌基因靶点，对其抑制可能预防或克服耐药性。
