RAPTOR up-regulation contributes to resistance of renal cancer cells to PI3K-mTOR inhibition

被引：26

作者：

Earwaker, Philip ^{[1
,3
]}

Anderson, Caroline ^{[1
]}

Willenbrock, Frances ^{[1
]}

Harris, Adrian L. ^{[2
]}

Protheroe, Andrew S. ^{[2
]}

Macaulay, Valentine M. ^{[1
,2
]}

机构：

[1] Dept Oncol, Oxford, England

[2] Churchill Hosp, Oxford Univ Hosp NHS Trust, Oxford Canc & Haematol Ctr, Oxford, England

[3] Univ Hosp Birmingham NHS Fdn Trust, Ctr Canc, Birmingham, W Midlands, England

来源：

PLOS ONE | 2018年 / 13卷 / 02期

关键词：

ADVANCED SOLID TUMORS; GROWTH-FACTOR RECEPTOR; HISTONE DEACETYLASE INHIBITOR; MTOR KINASE INHIBITORS; PHASE-II TRIAL; MAMMALIAN TARGET; TYROSINE KINASE; DUAL INHIBITOR; PROTEIN-KINASE; BREAST-CANCER;

D O I：

10.1371/journal.pone.0191890

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The outlook for patients with advanced renal cell cancer (RCC) has been improved by targeted agents including inhibitors of the PI3 kinase (PI3K)-AKT-mTOR axis, although treatment resistance is a major problem. Here, we aimed to understand how RCC cells acquire resistance to PI3K-mTOR inhibition. We used the RCC4 cell line to generate a model of in vitro resistance by continuous culture in PI3K-mTOR kinase inhibitor NVP-BEZ235 (BEZ235, Dactolisib). Resistant cells were cross-resistant to mTOR inhibitor AZD2014. Sensitivity was regained after 4 months drug withdrawal, and resistance was partially suppressed by HDAC inhibition, supporting an epigenetic mechanism. BEZ235-resistant cells up-regulated and/or activated numerous proteins including MET, ABL, Notch, IGF-1R, INSR and MEK/ERK. However, resistance was not reversed by inhibiting or depleting these pathways, suggesting that many induced changes were passengers not drivers of resistance. BEZ235 blocked phosphorylation of mTOR targets S6 and 4E-BP1 in parental cells, but 4E-BP1 remained phosphorylated in resistant cells, suggesting BEZ235-refractory mTORC1 activity. Consistent with this, resistant cells over-expressed mTORC1 component RAPTOR at the mRNA and protein level. Furthermore, BEZ235 resistance was suppressed by RAPTOR depletion, or allosteric mTORC1 inhibitor rapamycin. These data reveal that RAPTOR up-regulation contributes to PI3K-mTOR inhibitor resistance, and suggest that RAPTOR expression should be included in the pharmacodynamic assessment of mTOR kinase inhibitor trials.

引用

页数：22

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