PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma
PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma
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DOI：
10.1038/srep32992
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发表时间：
2016-09-13
影响因子：
4.6
通讯作者：
Salgia, Ravi
中科院分区：
文献类型：
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作者：
Kanteti, Rajani;Riehm, Jacob J.;Salgia, Ravi
恶性胸膜间皮瘤（MPM）是一种侵袭性癌症，通常与先前的石棉暴露有关。受体酪氨酸激酶（rtk）如MET及其下游靶点PI3K在大多数MPMs中过度表达和激活。在这里，我们研究了MET/ALK抑制剂克唑替尼与泛I类PI3K抑制剂BKM120或PI3K/mTOR双抑制剂GDC-0980在间皮瘤中的联合治疗效果。细胞活力结果显示，MPM细胞对克唑替尼、BKM120和GDC-0980单独使用时高度敏感，联合使用时抑制生长效果更好。用这些抑制剂治疗MPM细胞也能显著降低细胞迁移，并且它们的组合是协同的。单独使用BKM120或与克唑替尼联合治疗可诱导G2-M阻滞和细胞凋亡。克唑替尼和BKM120均能显著抑制MET和PI3K的活性，这可以通过MET、AKT和核糖体S6激酶磷酸化的降低来证明。通过PDX小鼠模型，我们发现克唑替尼与BKM120联合使用在抑制MPM肿瘤生长方面具有高度协同作用。总之，我们的研究结果表明，与单一药物相比，双重抑制PI3K和MET途径是治疗MPM的有效策略。
Malignant pleural mesothelioma (MPM) is an aggressive cancer that is commonly associated with prior asbestos exposure. Receptor tyrosine kinases (RTKs) such as MET and its downstream target PI3K are overexpressed and activated in a majority of MPMs. Here, we studied the combinatorial therapeutic efficacy of the MET/ALK inhibitor crizotinib, with either a pan-class I PI3K inhibitor, BKM120, or with a PI3K/mTOR dual inhibitor, GDC-0980, in mesothelioma. Cell viability results showed that MPM cells were highly sensitive to crizotinib, BKM120 and GDC-0980 when used individually and their combination was more effective in suppressing growth. Treatment of MPM cells with these inhibitors also significantly decreased cell migration, and the combination of them was synergistic. Treatment with BKM120 alone or in combination with crizotinib induced G2-M arrest and apoptosis. Both crizotinib and BKM120 strongly inhibited the activity of MET and PI3K as evidenced by the decreased phosphorylation of MET, AKT and ribosomal S6 kinase. Using a PDX mouse model, we showed that a combination of crizotinib with BKM120 was highly synergetic in inhibiting MPM tumor growth. In conclusion our findings suggest that dual inhibition of PI3K and MET pathway is an effective strategy in treating MPM as compared to a single agent.