PI3K/mTOR 的抑制会导致基质附着癌细胞产生适应性耐药。
Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells.
机构信息
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
出版信息
Cancer Cell. 2012 Feb 14;21(2):227-39. doi: 10.1016/j.ccr.2011.12.024.
Abstract
The PI3K/mTOR-pathway is the most commonly dysregulated pathway in epithelial cancers and represents an important target for cancer therapeutics. Here, we show that dual inhibition of PI3K/mTOR in ovarian cancer-spheroids leads to death of inner matrix-deprived cells, whereas matrix-attached cells are resistant. This matrix-associated resistance is mediated by drug-induced upregulation of cellular survival programs that involve both FOXO-regulated transcription and cap-independent translation. Inhibition of any one of several upregulated proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to PI3K/mTOR inhibition. These results demonstrate that acute adaptive responses to PI3K/mTOR inhibition in matrix-attached cells resemble well-conserved stress responses to nutrient and growth factor deprivation. Bypass of this resistance mechanism through rational design of drug combinations could significantly enhance PI3K-targeted drug efficacy.
摘要
PI3K/mTOR 通路是上皮性癌中最常失调的通路，也是癌症治疗的重要靶点。在这里，我们发现卵巢癌球体中 PI3K/mTOR 的双重抑制会导致内部基质剥夺细胞死亡，而基质附着的细胞则具有抗性。这种与基质相关的抗性是由药物诱导的细胞存活程序上调介导的，其中包括 FOXO 调节的转录和无 cap 依赖性翻译。抑制包括 Bcl-2、EGFR 或 IGF1R 在内的几种上调蛋白中的任何一种，均可消除对 PI3K/mTOR 抑制的抗性。这些结果表明，基质附着细胞中对 PI3K/mTOR 抑制的急性适应性反应类似于对营养和生长因子剥夺的保守应激反应。通过合理设计药物组合来绕过这种抗性机制，可以显著提高 PI3K 靶向药物的疗效。
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1
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Clin Proteomics. 2010 Dec;6(4):129-51. doi: 10.1007/s12014-010-9055-y.
2
Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase.转录和翻译后 HER3（ErbB3）的上调补偿了 HER2 酪氨酸激酶的抑制。
Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5021-6. doi: 10.1073/pnas.1016140108. Epub 2011 Mar 8.
3
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Integr Biol (Camb). 2011 Apr;3(4):279-96. doi: 10.1039/c0ib00144a. Epub 2011 Feb 22.
4
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Oncogene. 2011 Jun 2;30(22):2547-57. doi: 10.1038/onc.2010.626. Epub 2011 Jan 31.
5
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6
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7
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8
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9
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Oncogene. 2011 Feb 10;30(6):724-36. doi: 10.1038/onc.2010.445. Epub 2010 Oct 4.
10
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