Inhibition of Myc effectively targets KRAS mutation-positive lung cancer expressing high levels of Myc.
Inhibition of Myc effectively targets KRAS mutation-positive lung cancer expressing high levels of Myc.
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发表时间：
2010-10
影响因子：
2
通讯作者：
T. Fukazawa;Yutaka Maeda;J. Matsuoka;T. Yamatsuji;Kaoru Shigemitsu;I. Morita;F. Faiola;M. Durbin;L. Soucek;Y. Naomoto
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作者：
T. Fukazawa;Yutaka Maeda;J. Matsuoka;T. Yamatsuji;Kaoru Shigemitsu;I. Morita;F. Faiola;M. Durbin;L. Soucek;Y. Naomoto
Myc是促进肿瘤发生的致癌转录因子。最近，在KRAS突变引起的肺癌小鼠模型中，Myc的显性阴性形式（Omomyc）显示出引起肺肿瘤的消退，这表明Myc可能是治疗KRAS肺癌的潜在治疗靶点。然而，目前尚不清楚Omomyc是否也可以抑制携带类似KRAS突变的人类肺肿瘤的生长。在本研究中，我们证明Omomyc诱导KRAS突变的人肺腺癌A549细胞在体外和体内的细胞死亡。然而，Omomyc在也携带KRAS突变的人肺腺癌H441细胞中不诱导细胞死亡。有趣的是，A549细胞表达高水平的Myc，而H441细胞不表达。外源Myc与Omomyc在H441细胞中的共表达诱导细胞死亡，表明Omomyc需要高水平的Myc来诱导KRAS突变阳性肺腺癌中的细胞死亡。在这里，我们首次表明，显示高水平Myc的KRAS突变阳性肺癌可以通过抑制Myc反式激活功能来治疗。
Myc is an oncogenic transcription factor that promotes tumorigenesis. Recently, a dominant negative form of Myc (Omomyc) was shown to cause regression of lung tumors in a mouse model of lung cancer caused by KRAS mutation, suggesting that Myc might be a potential therapeutic target to treat the KRAS lung cancer. However, it is not yet known whether Omomyc can also inhibit the growth of human lung tumors that carry a similar KRAS mutation. In the present study, we demonstrate that Omomyc induces cell death of KRAS-mutated human lung adenocarcinoma A549 cells in vitro and in vivo. However, Omomyc does not induce cell death in human lung adenocarcinoma H441 cells that also carry the KRAS mutation. Interestingly, A549 cells express high levels of Myc, while H441 cells do not. Co-expression of exogenous Myc with Omomyc in H441 cells induces cell death, indicating that Omomyc requires high levels of Myc to induce cell death in KRAS mutation-positive lung adenocarcinoma. Here, we show for the first time that KRAS mutation-positive lung cancer displaying high levels of Myc could be treated by inhibiting Myc transactivation function.