Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2
Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2
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DOI：
10.1182/blood-2009-05-220889
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发表时间：
2009-10-01
期刊：
影响因子：
20.3
通讯作者：
Witzig, Thomas E.
中科院分区：
文献类型：
--
作者：
Gupta, Mamta;Ansell, Stephen M.;Witzig, Thomas E.
哺乳动物雷帕霉素靶蛋白（mTOR）已成为弥漫性大B细胞淋巴瘤（DLBCL）的重要治疗靶点，因为最近的研究表明，30%的复发患者对mTOR抑制剂有反应。为什么有些淋巴瘤是耐药的是不完全理解。在本研究中，我们证明了雷帕霉素抑制DLBCL细胞系和原发性肿瘤中的mTORC 1，但具有最小的细胞毒性。随后的研究表明，雷帕霉素也激活eIF 4 E和mTORC 2靶点Akt，这表明雷帕霉素耐药的潜在机制。此外，敲低mTORC 2组分rictor，而不是mTORC 1组分raptor，抑制雷帕霉素诱导的淋巴瘤细胞中Akt磷酸化。添加组蛋白脱乙酰酶抑制剂（HDI）LBH 589（LBH）通过阻断mTOR克服了雷帕霉素抗性，从而防止Akt活化。进一步的研究支持蛋白磷酸酶PP 1参与LBH介导的Akt去磷酸化，这可以通过敲低HDAC 3来模拟。这是第一次证明HDI如LBH可以通过拮抗mTORC 2激活的磷酸酶克服雷帕霉素抗性。这些结果为HDI和mTOR抑制剂联合治疗DLBCL的临床试验提供了机制依据。（血。2009; 114：2926-2935）
The mammalian target of rapamycin (mTOR) has emerged as an important therapeutic target for diffuse large B-cell lymphoma (DLBCL), as recent studies have demonstrated that 30% of relapsed patients respond to mTOR inhibitors. Why some lymphomas are resistant is incompletely understood. In the present study, we demonstrated that rapamycin inhibits mTORC1 in DLBCL lines and primary tumors but is minimally cytotoxic. Subsequent investigations revealed that rapa-mycin also activated eIF4E and the mTORC2 target Akt, suggesting a potential mechanism of rapamycin resistance. Furthermore, knockdown of the mTORC2 component rictor, but not the mTORC1 component raptor, inhibited rapamycin-induced Akt phosphorylation in lymphoma cells. Addition of the histone deacetylase inhibitor (HDI) LBH589 (LBH) overcame rapamycin resistance by blocking mTOR, thus preventing Akt activation. Further studies support the involvement of the protein phosphatase PP1 in LBH-mediated Akt dephosphorylation, which could be mimicked by knockdown of HDAC3. This is the first demonstration that a HDI such as LBH can overcome rapamycin resistance through a phosphatase that antagonizes mTORC2 activation. These results provide a mechanistic rationale for a clinical trial of a combination of HDI and mTOR inhibitors for DLBCL. (Blood. 2009; 114: 2926-2935)