Targeting HSP90 in ovarian cancers with multiple receptor tyrosine kinase coactivation.
Targeting HSP90 in ovarian cancers with multiple receptor tyrosine kinase coactivation.
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DOI：
10.1186/1476-4598-10-125
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发表时间：
2011-09-30
期刊：
影响因子：
37.3
通讯作者：
Wang A
中科院分区：
文献类型：
--
作者：
Jiao Y;Ou W;Meng F;Zhou H;Wang A
卵巢癌是所有妇科恶性肿瘤中死亡率最高的。受体酪氨酸激酶（receptor tyrosine kinases，RTK），包括EGFR、ERBB 2、PDGFR、VEGFR和MET，在卵巢癌的亚群中被激活，提示这些激酶可能代表新的治疗靶点。然而，临床试验尚未或仅部分显示EGFR、ERBB 2或PDGFR抑制剂治疗卵巢癌的益处。尽管在卵巢癌发病机制中存在多个RTK激活，但目前尚不清楚转化活性是否依赖于单个激酶癌蛋白或多个激酶的协调活性。我们假设多RTK激活的协调网络对于卵巢癌的肿瘤发生是重要的。在此，我们证明了多种RTK（EGFR、ERBB 2、ERBB 4、MET和/或AXL）在个体卵巢癌细胞系和原发性肿瘤中的共活化。我们还表明，协调抑制这种多激酶信号传导对卵巢癌的增殖和生存有显着更大的影响相比，抑制个别活化激酶。通过HSP 90抑制对这种多RTK信号传导的抑制导致深刻的促凋亡和抗增殖作用，并且与RTK下游PI 3-K/AKT/mTOR和RAF/MAPK信号传导的失活相关。这些研究表明，抗多重RTK策略可能有助于卵巢癌的治疗。
Ovarian cancer has the highest mortality rate of all gynecologic malignancy. The receptor tyrosine kinases (RTKs), including EGFR, ERBB2, PDGFR, VEGFR and MET, are activated in subsets of ovarian cancer, suggesting that these kinases might represent novel therapeutic targets. However, clinical trials have not or just partially shown benefit to ovarian cancers treated with EGFR, ERBB2, or PDGFR inhibitors. Despite multiple RTK activation in ovarian cancer pathogenesis, it is unclear whether transforming activity is dependent on an individual kinase oncoprotein or the coordinated activity of multiple kinases. We hypothesized that a coordinated network of multi-RTK activation is important for the tumorigenesis of ovarian cancers. Herein, we demonstrate co-activation of multiple RTKs (EGFR, ERBB2, ERBB4, MET and/or AXL) in individual ovarian cancer cell lines and primary tumors. We also show that coordinate inhibition of this multi-kinase signaling has substantially greater effect on ovarian cancer proliferation and survival, compared to inhibition of individual activated kinases. The inhibition of this multi-RTK signaling by HSP90 suppression results in profound pro-apoptotic and anti-proliferative effects, and is associated with the inactivation of RTK downstream PI3-K/AKT/mTOR and RAF/MAPK signaling. These studies suggest that anti-multiple RTK strategy could be useful in the treatment of ovarian cancer.
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影响因子：
7.3
作者：
Ahmed, Ashour Ahmed;Etemadmoghadam, Dariush;Temple, Jillian;Lynch, Andy G.;Riad, Mohamed;Sharma, Raghwa;Stewart, Colin;Fereday, Sian;Caldas, Carlos;DeFazio, Anna;Bowtell, David;Brenton, James D.
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Brenton, James D.
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影响因子：
8.8
作者：
Lassus, H;Sihto, H;Leminen, A;Nordling, S;Joensuu, H;Nupponen, NN;Butzow, R
通讯作者：
Butzow, R
影响因子：
11.2
作者：
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通讯作者：
Workman, Paul
影响因子：
10.3
作者：
Lee, Jeong-Won;Han, Hee Dong;Sood, Anil K.
通讯作者：
Sood, Anil K.