STAT3 is activated by JAK2 independent of key oncogenic driver mutations in non-small cell lung carcinoma.
STAT3 is activated by JAK2 independent of key oncogenic driver mutations in non-small cell lung carcinoma.
复制标题
DOI：
10.1371/journal.pone.0030820
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Mackeigan JP
中科院分区：
文献类型：
--
作者：
Looyenga BD;Hutchings D;Cherni I;Kingsley C;Weiss GJ;Mackeigan JP
STAT 3的组成性激活是包括非小细胞肺癌（NSCLC）在内的许多实体瘤的共同特征。虽然STAT 3的激活通常通过血液恶性肿瘤中JAK 2的体细胞突变来实现，但在实体瘤中通常不存在类似的突变。相反，以前的工作表明，实体瘤中的STAT 3激活更常见于由过度活跃的生长因子受体或自分泌细胞因子信号传导诱导。STAT 3激活与NSCLC中其他特征明确的致癌“驱动”突变之间的相互作用尚未完全表征，尽管已提出组成性STAT 3激活在对靶向这些致癌基因的各种小分子疗法的耐药性中发挥重要作用。在这项研究中，我们证明了STAT 3在人类NSCLC样本和各种NSCLC细胞系中被组成性激活，而不依赖于激活KRAS或酪氨酸激酶突变。我们进一步表明，gp 130/JAK 2信号通路的遗传或药理学抑制破坏了STAT 3的激活。有趣的是，用JAK 1/2抑制剂ruxolitinib处理NSCLC细胞对二维培养中的细胞增殖和活力没有影响，但在软琼脂和异种移植试验中抑制生长。这些数据表明，JAK 2/STAT 3信号传导在NSCLC中独立于已知的驱动突变发挥作用，并在肿瘤细胞行为中发挥关键作用，而选择性靶向这些驱动突变的药物可能无法有效抑制肿瘤细胞行为。
Constitutive activation of STAT3 is a common feature in many solid tumors including non-small cell lung carcinoma (NSCLC). While activation of STAT3 is commonly achieved by somatic mutations to JAK2 in hematologic malignancies, similar mutations are not often found in solid tumors. Previous work has instead suggested that STAT3 activation in solid tumors is more commonly induced by hyperactive growth factor receptors or autocrine cytokine signaling. The interplay between STAT3 activation and other well-characterized oncogenic “driver” mutations in NSCLC has not been fully characterized, though constitutive STAT3 activation has been proposed to play an important role in resistance to various small-molecule therapies that target these oncogenes. In this study we demonstrate that STAT3 is constitutively activated in human NSCLC samples and in a variety of NSCLC lines independent of activating KRAS or tyrosine kinase mutations. We further show that genetic or pharmacologic inhibition of the gp130/JAK2 signaling pathway disrupts activation of STAT3. Interestingly, treatment of NSCLC cells with the JAK1/2 inhibitor ruxolitinib has no effect on cell proliferation and viability in two-dimensional culture, but inhibits growth in soft agar and xenograft assays. These data demonstrate that JAK2/STAT3 signaling operates independent of known driver mutations in NSCLC and plays critical roles in tumor cell behavior that may not be effectively inhibited by drugs that selectively target these driver mutations.
登录
查看更多内容
表皮生长因子受体和KRAS突变对以前未经治疗的非小细胞肺癌患者的临床结果的影响：临床试验的在线肿瘤注册表的结果。
DOI：
10.1158/1078-0432.ccr-09-0888
发表时间：
2009-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jackman DM;Miller VA;Cioffredi LA;Yeap BY;Jänne PA;Riely GJ;Ruiz MG;Giaccone G;Sequist LV;Johnson BE
通讯作者：
Johnson BE
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.3
作者：
Bromberg, JF;Horvath, CM;Darnell, JE
通讯作者：
Darnell, JE
影响因子：
82.9
作者：
Chiarle, R;Simmons, WJ;Inghirami, G
通讯作者：
Inghirami, G
影响因子：
11.5
作者：
Chen, Kuen-Feng;Tai, Wei-Tien;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii