Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells (Cancer Cell, 2012, 21:227-239)

報告日期: 2012/11/23
報告時間: 15:10/16:00
報告學生: 黃馨慧
講評老師: 劉校生
附件下載: 下載[1247-1348734619-1.pdf] 

Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells

Taru Muranen,Laura M. Selfors,Devin T. Worster,Marcin P. Iwanicki,Loling Song,Fabiana C. Morales,

Sizhen Gao,Gordon B. Mills,and Joan S. Brugge.

Cancer Cell 21, 227–239, February 14, 2012

SpeakerShin-Huei Huang                             Date2012/11/23 15:10-16:00

                          CommentatorProf. Hsiao-Sheng Liu            PlaceRoom 602

 

Abstract

Epithelial cancer is common in various cancer types, and it is usually have dysregulated pi3k/mTOR pathway. Although targeting this pathway is applied for clinical therapies, it still has drugs resistance. In this paper, the author provided the possible mechanism to explain the resistance by high-throughput proteomics approaches and identified the combination of the drugs through 3D model system that more mimic the in vivo environment than 2D system to further use of clinical therapeutics. In 3D culture, ovarian cancer cells were treated with PI3K/mTOR inhibitor BEZ235 and induced a dichotomy in apoptosis between the drug-resistant matrix-attached outer cells and the inner matrix-deprived cells. The author performed reverse phase protein array (RPPA) analysis of 120 proteins and phosphoproteins to examine outer 3D tumor spheroid cells could be intrinsically drug resistant, or drug treatment could induce resistance. The results represented multiple prosurvival proteins, including several RTKs (EGFR, HER2, c-Kit, and IGF1R), cytoplasmic kinases (p-p90RSK, p-SrcY), antiapoptotic proteins (Bcl-2, XIAP1), and transcription factors (p-STAT3, p-STAT6, p-c-Jun, p-SMAD3) were upregulated after BEZ235 treatment. Inhibition of Bcl-2, IGF1R, or EGFR in combination with BEZ235 abrogates matrix protection, the author also found that many induced proteins are upregulated at the mRNA level through FOXO-dependent transcription. Furthermore, inhibition of the mTORC1 targeting 4E-BP1 correlates with upregulation of Bcl-2 and IGF1Rb and increases cap-independent translation. In addition to ovarian cancer cells, breast cancer cell lines also display the adaptive response to BEZ235 and are sensitive to combined PI3K/mTOR and Bcl-2 inhibition. In the end, mouse xenografts and primary ovarian and breast cancer patient samples show sensitivity to dual inhibition of PI3K/mTOR and Bcl-2, these results suggest that this drug combination could significantly enhance pi3k-target drug efficacy.

 

 Reference

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2.     Debnath, J., and Brugge, J.S. (2005). Modelling glandular epithelial cancers in three-dimensional cultures. Nat. Rev. Cancer 5, 675–688.