|Preclinical work on the MK-2206/rida combo that Merck has in trials:|
Akt Inhibitors MK-2206 and Nelfinavir Overcome mTOR Inhibitor Resistance in Diffuse Large B-cell Lymphoma
Adam M. Petrich 1, 2, Violetta Leshchenko 2, Pei-Yu Kuo 2, Bing Xia 2, Venu K. Thirukonda 1, 2, Netha Ulahannan 2, Shanisha Gordon 2, Melissa J. Fazzari 2, B. Hilda Ye 2, Joseph A. Sparano 1, 2, and Samir Parekh 1, 2 +Author Affiliations
Authors’ Affiliations: 1Montefiore Medical Center; and 2Albert Einstein College of Medicine, Bronx, New YorkCorresponding Author:
Samir Parekh, Albert Einstein College of Medicine, 111 East 210th Street Bronx, NY 10467. Phone: 718-920-4826; Fax: 718-798-7474; E-mail: firstname.lastname@example.org
AbstractPurpose: 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 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 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. Clin Cancer Res; 18(9); 1–11. ©2012 AACR.
FootnotesNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
Current address for A.M. Petrich: Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
Received June 10, 2011.Revision received January 9, 2012.Accepted February 3, 2012.©2012 American Association for Cancer Research.