Knockdown of oncogenic KRAS in non-small cell lung cancers suppresses tumor growth and sensitizes tumor cells to targeted therapy.
Knockdown of oncogenic KRAS in non-small cell lung cancers suppresses tumor growth and sensitizes tumor cells to targeted therapy.
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DOI：
10.1158/1535-7163.mct-10-0750
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发表时间：
2011-02
影响因子：
5.7
通讯作者：
Minna JD
中科院分区：
文献类型：
--
作者：
Sunaga N;Shames DS;Girard L;Peyton M;Larsen JE;Imai H;Soh J;Sato M;Yanagitani N;Kaira K;Xie Y;Gazdar AF;Mori M;Minna JD
致癌性KRAS存在于>25%的肺腺癌（非小细胞肺癌（NSCLC）的主要组织学亚型）中，并且是药物开发的重要靶标。为此，我们产生了四个NSCLC细胞系，其对致癌KRAS具有稳定的选择性敲低。正如预期的那样，致癌KRAS的稳定敲除导致KRAS突变NSCLC细胞中体外和体内肿瘤生长的抑制，但在具有野生型KRAS（但具有突变NRAS）的NSCLC细胞中不抑制。令人惊讶的是，我们没有看到大规模诱导细胞死亡，生长抑制作用也不完全。为了进一步了解NSCLC在选择性去除突变KRAS表达的情况下生长的能力，我们对具有或不具有突变KRAS敲低的NSCLC细胞系和具有或不具有致癌KRAS的等基因人支气管上皮细胞系（HBEC）进行了微阵列表达谱分析。我们发现，虽然突变KRAS敲低后MAPK通路显著下调，但这些NSCLC显示磷酸化STAT3和磷酸化EGFR水平升高，磷酸化Akt变化不定。此外，突变KRAS敲低使NSCLC对p38和EGFR抑制剂敏感。我们的研究结果表明，靶向致癌KRAS本身将是不够的治疗，但可能会提供抗KRAS策略与其他靶向药物相结合的可能性。
Oncogenic KRAS is found in >25% of lung adenocarcinomas, the major histologic subtype of non-small cell lung cancer (NSCLC), and is an important target for drug development. To this end, we generated four NSCLC lines with stable knockdown selective for oncogenic KRAS. As expected, stable knockdown of oncogenic KRAS led to inhibition of in vitro and in vivo tumor growth in the KRAS mutant NSCLC cells, but not in NSCLC cells that have wild-type KRAS (but mutant NRAS). Surprisingly, we did not see large-scale induction of cell death and the growth inhibitory effect was not complete. To further understand the ability of NSCLCs to grow despite selective removal of mutant KRAS expression, we performed microarray expression profiling of NSCLC cell lines with or without mutant KRAS knockdown and isogenic human bronchial epithelial cell lines (HBECs) with and without oncogenic KRAS. We found that while the MAPK pathway is significantly down-regulated after mutant KRAS knockdown, these NSCLCs showed increased levels of phospho-STAT3 and phospho-EGFR, and variable changes in phospho-Akt. In addition, mutant KRAS knockdown sensitized the NSCLCs to p38 and EGFR inhibitors. Our findings suggest that targeting oncogenic KRAS by itself will not be sufficient treatment but may offer possibilities of combining anti-KRAS strategies with other targeted drugs.