Small molecule inhibitors of IkappaB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling.
Constitutive activation of the NF-kappaB pathway is required for survival of the activated B cell-like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL). Here we show that a small molecule IkappaB kinase (IKK) inhibitor, PS-1145, and related compounds are toxic for ABC DLBCL cell lines but not for cell lines derived from the other prevalent form of DLBCL, germinal center B cell-like DLBCL. Treatment of ABC lines with these inhibitors rapidly induced a series of gene expression changes that were attributable to cessation of constitutive IKK activity, similar to changes induced by acute expression of genetic inhibitors of NF-kappaB, confirming the effectiveness and specificity of this compound. Before cell death, inhibition of IKK also induced features of apoptosis and an arrest in the G1 phase of the cell cycle. To test further the specificity of this toxicity, an inducible form of NF-kappaB was created by fusing the p65 NF-kappaB subunit with the ligand-binding domain of the estrogen receptor (p65-ERD). In the presence of tamoxifen, p65-ERD reversed the toxicity of IKK inhibition and restored expression of many NF-kappaB target genes. Another subgroup of DLBCL, primary mediastinal B-cell lymphoma (PMBL), also expresses NF-kappaB target genes, and treatment of a PMBL cell line with an IKK inhibitor was toxic and induced gene expression changes of a distinct group of NF-kappaB target genes. These studies validate the NF-kappaB pathway as a promising therapeutic target in ABC DLBCL, PMBL, and other lymphomas that depend on the activity of NF-kappaB for survival and proliferation.
Lam
Lloyd T
LT
Metabolism Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Davis
R Eric
RE
Pierce
Jackie
J
Hepperle
Michael
M
Xu
Yajun
Y
Hottelet
Maria
M
Nong
Yuhua
Y
Wen
Danyi
D
Adams
Julian
J
Dang
Lenny
L
Staudt
Louis M
LM
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002243:Carbolines / Q000494:pharmacology; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase; D020128:Inhibitory Concentration 50; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation
D000970:Antineoplastic Agents; D002243:Carbolines; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; C501460:MLX105; D016328:NF-kappa B; C456319:PS1145; D011725:Pyridines; D011960:Receptors, Estrogen; D013629:Tamoxifen; D007770:L-Lactate Dehydrogenase; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human