Akt inhibitors MK-2206 and nelfinavir overcome mTOR inhibitor resistance in diffuse large B-cell lymphoma

Adam M. Petrich, Violetta Leshchenko, Pei Yu Kuo, Bing Xia, Venu K. Thirukonda, Netha Ulahannan, Shanisha Gordon, Melissa J. Fazzari, B. Hilda Ye, Joseph A. Sparano, Samir Parekh

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Purpose: The mTOR pathway is constitutively activated in diffuse large B-cell lymphoma (DLBCL). mTOR inhibitors have activity in DLBCL, although response rates remain low. We evaluated DLBCL cell lines with differential resistance to the mTOR inhibitor rapamycin: (i) to identify gene expression profile(s) (GEP) associated with resistance to rapamycin, (ii) to understand mechanisms of rapamycin resistance, and (iii) to identify compounds likely to synergize with mTOR inhibitor. Experimental Design: We sought to identify a GEP of mTOR inhibitor 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 then 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 reliably distinguishing rapamycin-resistant from rapamycinsensitive 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 mTOR inhibitor resistance. Nelfinavir and MK-2206, chosen for their Akt-inhibitory properties, yielded synergistic inhibition of cell viability in combination with rapamycin in DLBCL cell lines, and potently inhibited phosphorylation of Akt and downstream targets of activated mTOR. Conclusions: GEP identifies DLBCL subsets resistant to mTOR inhibitor therapy. Combined targeting of mTOR and Akt suppresses activation of key components of the Akt/mTOR pathway and results in synergistic cytotoxicity. These findings are readily adaptable to clinical trials.

Original languageEnglish (US)
Pages (from-to)2534-2544
Number of pages11
JournalClinical Cancer Research
Volume18
Issue number9
DOIs
StatePublished - May 1 2012

Fingerprint

Nelfinavir
Lymphoma, Large B-Cell, Diffuse
Sirolimus
Cell Line
B-Lymphocyte Subsets
Gene Regulatory Networks
MK 2206
Transcriptome
Immunoassay
Cell Survival
Research Design
Phosphorylation
Clinical Trials

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Petrich, A. M., Leshchenko, V., Kuo, P. Y., Xia, B., Thirukonda, V. K., Ulahannan, N., ... Parekh, S. (2012). Akt inhibitors MK-2206 and nelfinavir overcome mTOR inhibitor resistance in diffuse large B-cell lymphoma. Clinical Cancer Research, 18(9), 2534-2544. https://doi.org/10.1158/1078-0432.CCR-11-1407

Akt inhibitors MK-2206 and nelfinavir overcome mTOR inhibitor resistance in diffuse large B-cell lymphoma. / Petrich, Adam M.; Leshchenko, Violetta; Kuo, Pei Yu; Xia, Bing; Thirukonda, Venu K.; Ulahannan, Netha; Gordon, Shanisha; Fazzari, Melissa J.; Ye, B. Hilda; Sparano, Joseph A.; Parekh, Samir.

In: Clinical Cancer Research, Vol. 18, No. 9, 01.05.2012, p. 2534-2544.

Research output: Contribution to journalArticle

Petrich, AM, Leshchenko, V, Kuo, PY, Xia, B, Thirukonda, VK, Ulahannan, N, Gordon, S, Fazzari, MJ, Ye, BH, Sparano, JA & Parekh, S 2012, 'Akt inhibitors MK-2206 and nelfinavir overcome mTOR inhibitor resistance in diffuse large B-cell lymphoma', Clinical Cancer Research, vol. 18, no. 9, pp. 2534-2544. https://doi.org/10.1158/1078-0432.CCR-11-1407
Petrich, Adam M. ; Leshchenko, Violetta ; Kuo, Pei Yu ; Xia, Bing ; Thirukonda, Venu K. ; Ulahannan, Netha ; Gordon, Shanisha ; Fazzari, Melissa J. ; Ye, B. Hilda ; Sparano, Joseph A. ; Parekh, Samir. / Akt inhibitors MK-2206 and nelfinavir overcome mTOR inhibitor resistance in diffuse large B-cell lymphoma. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 9. pp. 2534-2544.
@article{d72ac95d877f4f32aa76664c5bbef855,
title = "Akt inhibitors MK-2206 and nelfinavir overcome mTOR inhibitor resistance in diffuse large B-cell lymphoma",
abstract = "Purpose: The mTOR pathway is constitutively activated in diffuse large B-cell lymphoma (DLBCL). mTOR inhibitors have activity in DLBCL, although response rates remain low. We evaluated DLBCL cell lines with differential resistance to the mTOR inhibitor rapamycin: (i) to identify gene expression profile(s) (GEP) associated with resistance to rapamycin, (ii) to understand mechanisms of rapamycin resistance, and (iii) to identify compounds likely to synergize with mTOR inhibitor. Experimental Design: We sought to identify a GEP of mTOR inhibitor 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 then 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 reliably distinguishing rapamycin-resistant from rapamycinsensitive 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 mTOR inhibitor resistance. Nelfinavir and MK-2206, chosen for their Akt-inhibitory properties, yielded synergistic inhibition of cell viability in combination with rapamycin in DLBCL cell lines, and potently inhibited phosphorylation of Akt and downstream targets of activated mTOR. Conclusions: GEP identifies DLBCL subsets resistant to mTOR inhibitor therapy. Combined targeting of mTOR and Akt suppresses activation of key components of the Akt/mTOR pathway and results in synergistic cytotoxicity. These findings are readily adaptable to clinical trials.",
author = "Petrich, {Adam M.} and Violetta Leshchenko and Kuo, {Pei Yu} and Bing Xia and Thirukonda, {Venu K.} and Netha Ulahannan and Shanisha Gordon and Fazzari, {Melissa J.} and Ye, {B. Hilda} and Sparano, {Joseph A.} and Samir Parekh",
year = "2012",
month = "5",
day = "1",
doi = "10.1158/1078-0432.CCR-11-1407",
language = "English (US)",
volume = "18",
pages = "2534--2544",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Akt inhibitors MK-2206 and nelfinavir overcome mTOR inhibitor resistance in diffuse large B-cell lymphoma

AU - Petrich, Adam M.

AU - Leshchenko, Violetta

AU - Kuo, Pei Yu

AU - Xia, Bing

AU - Thirukonda, Venu K.

AU - Ulahannan, Netha

AU - Gordon, Shanisha

AU - Fazzari, Melissa J.

AU - Ye, B. Hilda

AU - Sparano, Joseph A.

AU - Parekh, Samir

PY - 2012/5/1

Y1 - 2012/5/1

N2 - Purpose: The mTOR pathway is constitutively activated in diffuse large B-cell lymphoma (DLBCL). mTOR inhibitors have activity in DLBCL, although response rates remain low. We evaluated DLBCL cell lines with differential resistance to the mTOR inhibitor rapamycin: (i) to identify gene expression profile(s) (GEP) associated with resistance to rapamycin, (ii) to understand mechanisms of rapamycin resistance, and (iii) to identify compounds likely to synergize with mTOR inhibitor. Experimental Design: We sought to identify a GEP of mTOR inhibitor 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 then 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 reliably distinguishing rapamycin-resistant from rapamycinsensitive 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 mTOR inhibitor resistance. Nelfinavir and MK-2206, chosen for their Akt-inhibitory properties, yielded synergistic inhibition of cell viability in combination with rapamycin in DLBCL cell lines, and potently inhibited phosphorylation of Akt and downstream targets of activated mTOR. Conclusions: GEP identifies DLBCL subsets resistant to mTOR inhibitor therapy. Combined targeting of mTOR and Akt suppresses activation of key components of the Akt/mTOR pathway and results in synergistic cytotoxicity. These findings are readily adaptable to clinical trials.

AB - Purpose: The mTOR pathway is constitutively activated in diffuse large B-cell lymphoma (DLBCL). mTOR inhibitors have activity in DLBCL, although response rates remain low. We evaluated DLBCL cell lines with differential resistance to the mTOR inhibitor rapamycin: (i) to identify gene expression profile(s) (GEP) associated with resistance to rapamycin, (ii) to understand mechanisms of rapamycin resistance, and (iii) to identify compounds likely to synergize with mTOR inhibitor. Experimental Design: We sought to identify a GEP of mTOR inhibitor 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 then 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 reliably distinguishing rapamycin-resistant from rapamycinsensitive 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 mTOR inhibitor resistance. Nelfinavir and MK-2206, chosen for their Akt-inhibitory properties, yielded synergistic inhibition of cell viability in combination with rapamycin in DLBCL cell lines, and potently inhibited phosphorylation of Akt and downstream targets of activated mTOR. Conclusions: GEP identifies DLBCL subsets resistant to mTOR inhibitor therapy. Combined targeting of mTOR and Akt suppresses activation of key components of the Akt/mTOR pathway and results in synergistic cytotoxicity. These findings are readily adaptable to clinical trials.

UR - http://www.scopus.com/inward/record.url?scp=84860511277&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860511277&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-11-1407

DO - 10.1158/1078-0432.CCR-11-1407

M3 - Article

VL - 18

SP - 2534

EP - 2544

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 9

ER -