Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer.
Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer.
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DOI：
10.1038/onc.2012.355
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发表时间：
2013-07-18
期刊：
影响因子：
8
通讯作者：
Graham, D. K.
中科院分区：
文献类型：
--
作者：
Linger, R. M. A.;Cohen, R. A.;Cummings, C. T.;Sather, S.;Migdall-Wilson, J.;Middleton, D. H. G.;Lu, X.;Baron, A. E.;Franklin, W. A.;Merrick, D. T.;Jedlicka, P.;DeRyckere, D.;Heasley, L. E.;Graham, D. K.
非小细胞肺癌（NSCLC）是一种普遍且毁灭性的疾病，其夺去的生命比乳腺癌、前列腺癌、结肠癌和胰腺癌加起来还要多。目前的研究表明，标准的化疗方案已经优化到最大的效率。有希望的新治疗策略包括针对非小细胞肺癌亚群中存在的分子畸变的新型药物。我们评估了88个不同组织学的人类非小细胞肺癌肿瘤，发现Mer和Axl受体酪氨酸激酶（rtk）相对于周围正常肺组织分别在69%和93%的肿瘤中过表达。Mer和Axl在NSCLC细胞系中也经常过表达和激活。配体依赖性Mer或Axl激活刺激MAPK、AKT和FAK信号通路，表明这些rtk在多种致癌过程中发挥作用。此外，我们还发现了一个新的促生存通路，包括AKT、CREB、Bcl-xL、survivin和bcl -2，该通路位于Mer的下游，受Axl信号的差异调节。我们证明shRNA敲低Mer或Axl可显著减少裸鼠皮下异种移植物的非小细胞肺癌集落形成和生长。Mer或Axl敲低也通过促进细胞凋亡改善了体外NSCLC对化疗药物的敏感性。当比较Mer和Axl敲低的作用时，Mer抑制表现出更完全的肿瘤生长阻断，而Axl敲低更有力地改善了化疗敏感性。这些结果表明Mer和Axl在NSCLC中发挥互补和重叠的作用，并提示针对这两种rtk的治疗策略可能比单靶向药物更有效。我们的研究结果证实了Mer和Axl是NSCLC的潜在治疗靶点，并为开发选择性抑制Mer和/或Axl的新型治疗化合物提供了理由。
Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon, and pancreatic cancers combined. Current research suggests that standard chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT, and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway—involving AKT, CREB, Bcl-xL, survivin, and Bcl-2—downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that shRNA knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl play complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl.
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有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.8
作者：
Demarchi, F;Verardo, R;Schneider, C
通讯作者：
Schneider, C
影响因子：
8
作者：
Arriola, EL;Rodriguez-Lopez, AM;Chresta, CM
通讯作者：
Chresta, CM
影响因子：
11.2
作者：
Aggarwal, Sita;Kim, Seung-Wook;Koo, Ja Seok
通讯作者：
Koo, Ja Seok
DOI：
10.1073/pnas.0909333107
发表时间：
2010-01-19
影响因子：
11.1
作者：
Gjerdrum, Christine;Tiron, Crina;Lorens, James B.
通讯作者：
Lorens, James B.