title: Temsirolimus inhibits cell growth in combination with inhibitors of the B-cell receptor pathway.
abstract: Lately, mTOR inhibitors have gained clinical relevance in malignant lymphoma. Still, rapamycin derivatives may activate a pro-survival feedback loop through PI3K-Akt. In this current study, temsirolimus effectively reduced cell growth in GCB and ABC diffuse large cell B-cell lymphoma (GCB=30-66%, ABC=45-57%). Combination treatment with the PI3K-δ inhibitor idelalisib additively effected ABC and GCB lymphoma (GCB=16-38%, ABC=25-50%). Since Bruton's Tyrosine Kinase (BTK) plays a significant role for the survival of ABC lymphoma, this study also combined the BTK inhibitor ibrutinib with temsirolimus, which resulted in additive cell growth reduction (ibrutinib 50%, temsirolimus 44%, combination 25%) in ABC lymphoma. In contrast, bortezomib, which has been shown previously to be efficient in ABC lymphoma, revealed an antagonistic effect with temsirolimus in some GCB lymphoma (temsirolimus 53%, temsirolimus+bortezomib 63%). Western blot analysis identified the increase of phosphorylated pro-survival kinases Akt and PDK as a possible underlying mechanism of this interaction.
authors.affiliation: a Department of Internal Medicine III , University Hospital Munich-Großhadern , Germany.|b Clinical Cooperative Group Leukemia, Helmholtz Zentrum , Munich , Germany.
authors.forename: Anna-Katharina
authors.initials: AK
authors.lastname: Zoellner
authors.affiliation: b Clinical Cooperative Group Leukemia, Helmholtz Zentrum , Munich , Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Bayerl
authors.affiliation: b Clinical Cooperative Group Leukemia, Helmholtz Zentrum , Munich , Germany.
authors.forename: Grit
authors.initials: G
authors.lastname: Hutter
authors.affiliation: b Clinical Cooperative Group Leukemia, Helmholtz Zentrum , Munich , Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Zimmermann
authors.affiliation: a Department of Internal Medicine III , University Hospital Munich-Großhadern , Germany.|b Clinical Cooperative Group Leukemia, Helmholtz Zentrum , Munich , Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.affiliation: a Department of Internal Medicine III , University Hospital Munich-Großhadern , Germany.|b Clinical Cooperative Group Leukemia, Helmholtz Zentrum , Munich , Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dreyling
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004357:Drug Synergism; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000225:Adenine; D000970:Antineoplastic Agents; D000069286:Bortezomib; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones; D011947:Receptors, Antigen, B-Cell; D020123:Sirolimus; C551803:ibrutinib; C401859:temsirolimus; C552946:idelalisib
keywords: DLBCL; PI3K; mTOR; temsirolimus