Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Neoplasia. 2011 Jan;13(1):12-22. doi: 10.1593/neo.101156.
The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR) and MET are activated in subsets of mesothelioma, suggesting that these kinases might represent novel therapeutic targets in this notoriously chemotherapy-resistant cancer. However, clinical trials have shown little activity for EGFR inhibitors in mesothelioma. Despite the evidence for RTK activation in mesothelioma pathogenesis, it is unclear whether transforming activity is dependent on an individual kinase oncoprotein or the coordinated activity of multiple kinases. Using phospho-RTK and immunoblot assays, we herein demonstrate activation of multiple RTKs (EGFR, MET, AXL, and ERBB3) in individual mesothelioma cell lines but not in normal mesothelioma cells. Inhibition of mesothelioma multi-RTK signaling was accomplished using combinations of RTK direct inhibitors or by inhibition of the RTK chaperone, heat shock protein 90 (HSP90). Multi-RTK inhibition by the HSP90 inhibitor 17-allyloamino-17-demethoxygeldanamycin (17-AAG) had a substantially greater effect on mesothelioma proliferation and survival compared with inhibition of individual activated RTKs. HSP90 inhibition also suppressed phosphorylation of downstream signaling intermediates (AKT, mitogen-activated protein kinase, and S6); upregulated the p53, p21, and p27 cell cycle checkpoints; induced G(2) phase arrest; induced caspase 3/7 activity; and led to an increase in the sub-G(1) apoptotic population. These compelling proapoptotic and antiproliferative responses indicate that HSP90 inhibition warrants clinical evaluation as a novel therapeutic strategy in mesothelioma.
受体酪氨酸激酶（RTKs）表皮生长因子受体（EGFR）和 MET 在间皮瘤的亚群中被激活，这表明这些激酶可能代表这种化疗耐药性癌症的新的治疗靶点。然而，临床试验表明 EGFR 抑制剂在间皮瘤中的活性有限。尽管有证据表明 RTK 在间皮瘤发病机制中被激活，但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。通过磷酸化 RTK 和免疫印迹分析，我们在此证明了多个 RTKs（EGFR、MET、AXL 和 ERBB3）在单个间皮瘤细胞系中被激活，但在正常间皮瘤细胞中没有被激活。通过 RTK 直接抑制剂的组合或通过抑制 RTK 伴侣热休克蛋白 90（HSP90）来抑制间皮瘤多 RTK 信号传导。HSP90 抑制剂 17-allyloamino-17-demethoxygeldanamycin（17-AAG）对间皮瘤增殖和存活的多 RTK 抑制作用明显大于对单个激活的 RTK 的抑制作用。HSP90 抑制还抑制了下游信号转导中间物（AKT、丝裂原激活蛋白激酶和 S6）的磷酸化；上调了 p53、p21 和 p27 细胞周期检查点；诱导 G2 期阻滞；诱导 caspase 3/7 活性；并导致亚 G1 凋亡细胞群增加。这些强烈的促凋亡和抗增殖反应表明，HSP90 抑制值得作为一种新的治疗策略在间皮瘤中进行临床评估。
