Akt Inhibitors MK-2206 and Nelfinavir Overcome mTOR Inhibitor Resistance in Diffuse Large B-cell Lymphoma

• Published in: Clinical cancer research Vol. 18; no. 9; pp. 2534 - 2544
• Main Authors: PETRICH, Adam M, LESHCHENKO, Violetta, PAREKH, Samir, KUO, Pei-Yu, BING XIA, THIRUKONDA, Venu K, ULAHANNAN, Netha, GORDON, Shanisha, FAZZARI, Melissa J, YE, B. Hilda, SPARANO, Joseph A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.2012
• Subjects: AKT protein; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Clinical trials; Cytotoxicity; double prime B-cell lymphoma; Drug Resistance, Neoplasm - drug effects; Flow Cytometry; Fluorescent Antibody Technique; Gene expression; Gene Expression Profiling; Hematologic and hematopoietic diseases; Heterocyclic Compounds, 3-Ring - pharmacology; HIV Protease Inhibitors - pharmacology; Humans; Immunoassays; Immunoenzyme Techniques; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; Medical sciences; Nelfinavir; Nelfinavir - pharmacology; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction - drug effects; Sirolimus - pharmacology; Synergism; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Enzyme; Enzyme inhibitor; B cell neoplasm; Malignant hemopathy; Non Hodgkin lymphoma; Resistance; Peptidases; AKT inhibitor; Lymphoproliferative syndrome; Nelfinavir; mTOR inhibitor; Hydrolases; Diffuse large B cell lymphoma; Protease inhibitor; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-1407

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. 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. 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. 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.