Yazarlar : Petrich AM, Leshchenko V, Kuo PY et al

Yayın : Clin Cancer Res.

Yayın Yılı : 2012

Pubmed Linki : http://www.ncbi.nlm.nih.gov/pubmed/22338016

Konu : Lenfoma

Literatür İçeriği :  

Abstract

PURPOSE:

The mTOR (mammalian Target of Rapamycin) pathway is constitutively activated in Diffuse Large B-Cell Lymphoma (DLBCL). mTOR inhibitors (mTORi) have activity in DLBCL, although response rates remain low. We evaluated DLBCL cell lines with differential resistance to the mTORi Rapamycin, in order to (A) identify gene-expression profile(s) (GEP) associated with resistance to Rapamycin, (B) understand mechanisms of Rapamycin resistance, and (C) identify compounds that synergize with mTORi.

EXPERIMENTAL DESIGN:

We sought to identify a GEP of mTORi resistance by stratification of eight DLBCL cell lines with respect to response to Rapamycin. Then, using pathway analysis and connectivity mapping, we sought targets likely accounting for this resistance, and compounds likely to overcome it. We evaluated two compounds thus identified for their potential to synergize with Rapamycin in DLBCL, and confirmed mechanisms of activity with standard immunoassays.

RESULTS:

We identified a GEP capable of distinguishing Rapamycin resistant from Rapamycin sensitive DLBCL cell lines. Pathway analysis identified Akt as central to the differentially expressed gene network. Connectivity mapping identified compounds targeting Akt as having a high likelihood of reversing the GEP associated with mTORi resistance. Nelfinavir and MK-2206, chosen for their Akt-inhibitory properties, synergistically inhibited cell viability in combination with Rapamycin in DLBCL cell lines, and potently inhibited phosphorylation of Akt and targets of activated mTOR.

CONCLUSIONS:

GEP identifies DLBCL subsets resistant to mTORi therapy. Combined targeting of mTOR and Akt suppresses key components of the Akt/mTOR pathway and results in synergistic cytotoxicity. These findings are readily adaptable to clinical trials.

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