A mechanism for synergy with combined mTOR and PI3 kinase inhibitors.
A mechanism for synergy with combined mTOR and PI3 kinase inhibitors.
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DOI：
10.1371/journal.pone.0026343
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Leslie KK
中科院分区：
文献类型：
--
作者：
Yang S;Xiao X;Meng X;Leslie KK
哺乳动物雷帕霉素靶蛋白（mTOR）信号转导的失调已在许多人类癌症中发现，特别是那些具有肿瘤抑制因子PTEN缺失的癌症。然而，mTORC1抑制剂如替西罗莫司在单独使用时仅具有适度的活性，并且可能通过激活上游mTORC2和Akt诱导获得性耐药性。其他不依赖PI3K/Akt/mTOR信号传导存活的肿瘤主要是耐药的。本研究检验了以下假设：替西罗莫司的有限临床疗效是由于Akt下游生存信号传导途径的代偿性增加以及mTOR下游4E-BP1控制的增殖过程的不完全阻断。我们探索了在替西罗莫司中加入PI3K抑制剂，并确定了组合协同作用的机制。增殖测定显示，与单独用任何试剂处理的细胞相比，BEZ235（双重PI3K/mTOR抑制剂）或ZSTK474（泛PI3K抑制剂）与坦罗莫司组合协同抑制细胞生长。共处理导致G0/G1细胞周期停滞和p27上调。细胞死亡通过大量的自噬和随后的凋亡发生。虽然分子分析显示，在大多数情况下，对坦罗莫司单独的敏感性在具有由PTEN失活引起的高基础磷酸化Akt的细胞中最显著，但将PI3K抑制剂与坦罗莫司组合防止了补偿性Akt磷酸化并协同增强了细胞死亡，而不管PTEN状态如何。协同作用的另一个分子相关性是发现替西罗莫司单独治疗阻断下游S6激酶信号传导，但不阻断4E-BP1。加入BEZ235完全消除4E-BP1磷酸化。我们的结论是，PI3K抑制剂的加入克服了细胞对mTORC 1抑制剂的耐药性，而不管PTEN状态如何，从而大大扩展了可能有反应的肿瘤的分子表型。
Dysregulation of the mammalian target of rapamycin (mTOR) signaling has been found in many human cancers, particularly those with loss of the tumor suppressor PTEN. However, mTORC1 inhibitors such as temsirolimus have only modest activity when used alone and may induce acquired resistance by activating upstream mTORC2 and Akt. Other tumors that do not depend upon PI3K/Akt/mTOR signaling for survival are primarily resistant. This study tested the hypothesis that the limited clinical efficacy of temsirolimus is due to a compensatory increase in survival signaling pathways downstream of Akt as well as an incomplete block of 4E-BP1-controlled proliferative processes downstream of mTOR. We explored the addition of a PI3K inhibitor to temsirolimus and identified the mechanism of combinatorial synergy. Proliferation assays revealed that BEZ235 (dual PI3K/mTOR inhibitor) or ZSTK474 (pan PI3K inhibitor) combined with temsirolimus synergistically inhibited cell growth compared to cells treated with any of the agents alone. Co-treatment resulted in G0/G1 cell cycle arrest and up-regulation of p27. Cell death occurred through massive autophagy and subsequent apoptosis. While molecular profiling revealed that, in most cases, sensitivity to temsirolimus alone was most marked in cells with high basal phospho-Akt resulting from PTEN inactivation, combining a PI3K inhibitor with temsirolimus prevented compensatory Akt phosphorylation and synergistically enhanced cell death regardless of PTEN status. Another molecular correlate of synergy was the finding that temsirolimus treatment alone blocks downstream S6 kinase signaling, but not 4E-BP1. Adding BEZ235 completely abrogated 4E-BP1 phosphorylation. We conclude that the addition of a PI3K inhibitor overcomes cellular resistance to mTORC1 inhibitors regardless of PTEN status, and thus substantially expands the molecular phenotype of tumors likely to respond.
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