Dual targeting of the PI3K/Akt/mTOR pathway as an antitumor strategy in Waldenstrom macroglobulinemia
Dual targeting of the PI3K/Akt/mTOR pathway as an antitumor strategy in Waldenstrom macroglobulinemia
复制标题
DOI：
10.1182/blood-2009-07-235747
复制
发表时间：
2010-01-21
期刊：
影响因子：
20.3
通讯作者：
Ghobrial, Irene M.
中科院分区：
文献类型：
--
作者：
Roccaro, Aldo M.;Sacco, Antonio;Ghobrial, Irene M.
我们先前已经显示了哺乳动物雷帕霉素靶蛋白（mTOR）复合物1抑制剂在瓦尔登斯特伦巨球蛋白血症（WM）中的临床活性。然而，50%的患者对治疗没有反应。因此，我们研究了磷酸肌醇3-激酶（PI 3 K）/Akt/mTOR在WM中的激活机制，以及克服治疗抵抗的机制。我们首先证明了原代WM细胞显示PI 3 K/Akt通路的组成性激活，这得到了磷酸盐和张力蛋白同源物肿瘤抑制基因（PTEN）在基因和蛋白水平表达降低以及Akt和mTOR组成性激活的支持。我们说明，与单独抑制PI 3 K或mTOR通路相比，新型抑制剂NVP-BEZ 235对PI 3 K/mTOR通路的双重靶向对WM细胞显示出更高的细胞毒性。此外，NVP-BEZ 235抑制了rictor和raptor，从而消除了rictor诱导的Akt磷酸化。NVP-BEZ 235还通过靶向叉头盒转录因子以半胱天冬酶依赖性和非依赖性方式在WM细胞中诱导显著的细胞毒性。此外，NVP-BEZ 235在骨髓微环境中靶向WM细胞，导致显著抑制体外迁移、粘附和体内归巢。因此，这些研究表明，PI 3 K/mTOR通路的双重靶向是具有PI 3 K/mTOR信号级联激活的肿瘤（例如WM）的靶向治疗的更好方式。（血。2010; 115：559-569）
We have previously shown clinical activity of a mammalian target of rapamycin (mTOR) complex 1 inhibitor in Waldenstrom macroglobulinemia (WM). However, 50% of patients did not respond to therapy. We therefore examined mechanisms of activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR in WM, and mechanisms of overcoming resistance to therapy. We first demonstrated that primary WM cells show constitutive activation of the PI3K/Akt pathway, supported by decreased expression of phosphate and tensin homolog tumor suppressor gene (PTEN) at the gene and protein levels, together with constitutive activation of Akt and mTOR. We illustrated that dual targeting of the PI3K/mTOR pathway by the novel inhibitor NVP-BEZ235 showed higher cytotoxicity on WM cells compared with inhibition of the PI3K or mTOR pathways alone. In addition, NVP-BEZ235 inhibited both rictor and raptor, thus abrogating the rictor-induced Akt phosphorylation. NVP-BEZ235 also induced significant cytotoxicity in WM cells in a caspase-dependent and -independent manner, through targeting the Forkhead box transcription factors. In addition, NVP-BEZ235 targeted WM cells in the context of bone marrow microenvironment, leading to significant inhibition of migration, adhesion in vitro, and homing in vivo. These studies therefore show that dual targeting of the PI3K/mTOR pathway is a better modality of targeted therapy for tumors that harbor activation of the PI3K/mTOR signaling cascade, such as WM. (Blood. 2010; 115: 559-569)