Inhibition of TWIST1 leads to activation of oncogene-induced senescence in oncogene-driven non-small cell lung cancer.
Inhibition of TWIST1 leads to activation of oncogene-induced senescence in oncogene-driven non-small cell lung cancer.
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DOI：
10.1158/1541-7786.mcr-12-0456
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Rudin CM
中科院分区：
文献类型：
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作者：
Burns TF;Dobromilskaya I;Murphy SC;Gajula RP;Thiyagarajan S;Chatley SN;Aziz K;Cho YJ;Tran PT;Rudin CM
大部分非小细胞肺癌（NSCLC）依赖于定义的致癌驱动突变。尽管EGFR和EML 4-ALK驱动的NSCLC存在靶向药物，但没有靶向最常见的驱动突变KRAS的治疗。此外，几乎普遍观察到对当前可靶向的驱动突变的获得性抗性。显然，需要一种新的治疗方法来靶向癌基因驱动的NSCLC。我们最近证明了碱性螺旋-环-螺旋转录因子Twist 1与突变型Kras合作在转基因小鼠模型中诱导肺腺癌，并且在这些模型中Twist 1的抑制导致Kras诱导的衰老。在本研究中，我们研究了TWIST 1在癌基因驱动的人类NSCLC中的作用。在KRAS突变的人NSCLC细胞系中，TWIST 1的沉默导致显著的生长抑制和潜在癌基因诱导的衰老程序的激活，或者在某些情况下导致细胞凋亡。在EGFR突变驱动和c-Met扩增的NSCLC细胞系中观察到相似的效应。通过沉默TWIST 1抑制生长独立于p53或p16突变状态，并且不需要先前定义的衰老介质p21和p27，也不能通过SKP 2的过表达来挽救这种表型。在异种移植模型中，TWIST 1的沉默导致KRAS突变体、EGFR突变体和c-Met扩增NSCLC的显著生长抑制。值得注意的是，TWIST 1的可诱导沉默导致已建立的KRAS突变肿瘤的显著生长抑制。总之，这些发现表明，在癌基因驱动依赖性NSCLC中沉默TWIST 1代表了一种新的有希望的治疗策略。
A large fraction of non-small cell lung cancers (NSCLC) are dependent on defined oncogenic driver mutations. Although targeted agents exist for EGFR- and EML4-ALK-driven NSCLC, no therapies target the most frequently found driver mutation, KRAS. Furthermore, acquired resistance to the currently targetable driver mutations is nearly universally observed. Clearly a novel therapeutic approach is needed to target oncogene driven NSCLC. We recently demonstrated that the basic helix-loop-helix transcription factor Twist1 cooperates with mutant Kras to induce lung adenocarcinoma in transgenic mouse models and that inhibition of Twist1 in these models led to Kras-induced senescence. In the current study, we examine the role of TWIST1 in oncogene driven human NSCLC. Silencing of TWIST1 in KRAS mutant human NSCLC cell lines resulted in dramatic growth inhibition and either activation of a latent oncogene-induced senescence program or in some cases, apoptosis. Similar effects were observed in EGFR mutation driven and c-Met amplified NSCLC cell lines. Growth inhibition by silencing of TWIST1 was independent of p53 or p16 mutational status and did not require previously defined mediators of senescence, p21 and p27, nor could this phenotype be rescued by overexpression of SKP2. In xenograft models, silencing of TWIST1 resulted in significant growth inhibition of KRAS mutant, EGFR mutant and c-Met amplified NSCLC. Remarkably, inducible silencing of TWIST1 resulted in significant growth inhibition of established KRAS mutant tumors. Together these findings suggest that silencing of TWIST1 in oncogene driver dependent NSCLC represents a novel and promising therapeutic strategy.