title: Cell Panel Profiling Reveals Conserved Therapeutic Clusters and Differentiates the Mechanism of Action of Different PI3K/mTOR, Aurora Kinase and EZH2 Inhibitors.
abstract: Cancer cell line panels are important tools to characterize the in vitro activity of new investigational drugs. Here, we present the inhibition profiles of 122 anticancer agents in proliferation assays with 44 or 66 genetically characterized cancer cell lines from diverse tumor tissues (Oncolines). The library includes 29 cytotoxics, 68 kinase inhibitors, and 11 epigenetic modulators. For 38 compounds this is the first comparative profiling in a cell line panel. By strictly maintaining optimized assay protocols, biological variation was kept to a minimum. Replicate profiles of 16 agents over three years show a high average Pearson correlation of 0.8 using IC50values and 0.9 using GI50values. Good correlations were observed with other panels. Curve fitting appears a large source of variation. Hierarchical clustering revealed 44 basic clusters, of which 26 contain compounds with common mechanisms of action, of which 9 were not reported before, including TTK, BET and two clusters of EZH2 inhibitors. To investigate unexpected clusterings, sets of BTK, Aurora and PI3K inhibitors were profiled in biochemical enzyme activity assays and surface plasmon resonance binding assays. The BTK inhibitor ibrutinib clusters with EGFR inhibitors, because it cross-reacts with EGFR. Aurora kinase inhibitors separate into two clusters, related to Aurora A or pan-Aurora selectivity. Similarly, 12 inhibitors in the PI3K/AKT/mTOR pathway separated into different clusters, reflecting biochemical selectivity (pan-PI3K, PI3Kβγδ-isoform selective or mTOR-selective). Of these, only allosteric mTOR inhibitors preferentially targeted PTEN-mutated cell lines. This shows that cell line profiling is an excellent tool for the unbiased classification of antiproliferative compounds. Mol Cancer Ther; 15(12); 3097-109. ©2016 AACR.
authors: Netherlands Translational Research Center B.V., Kloosterstraat, the Netherlands.
authors: Joost C M
authors: JC
authors: Uitdehaag
authors: Netherlands Translational Research Center B.V., Kloosterstraat, the Netherlands.
authors: Jeroen A D M
authors: JA
authors: de Roos
authors: Netherlands Translational Research Center B.V., Kloosterstraat, the Netherlands.
authors: Martine B W
authors: MB
authors: Prinsen
authors: Netherlands Translational Research Center B.V., Kloosterstraat, the Netherlands.
authors: Nicole
authors: N
authors: Willemsen-Seegers
authors: Netherlands Translational Research Center B.V., Kloosterstraat, the Netherlands.
authors: Judith R F
authors: JR
authors: de Vetter
authors: Netherlands Translational Research Center B.V., Kloosterstraat, the Netherlands.
authors: Jelle
authors: J
authors: Dylus
authors: Netherlands Translational Research Center B.V., Kloosterstraat, the Netherlands.
authors: Antoon M
authors: AM
authors: van Doornmalen
authors: Netherlands Translational Research Center B.V., Kloosterstraat, the Netherlands.
authors: Jeffrey
authors: J
authors: Kooijman
authors: Carna Biosciences, Inc., Kobe, Japan.
authors: Masaaki
authors: M
authors: Sawa
authors: Netherlands Translational Research Center B.V., Kloosterstraat, the Netherlands.
authors: Suzanne J C
authors: SJ
authors: van Gerwen
authors: Netherlands Translational Research Center B.V., Kloosterstraat, the Netherlands.
authors: Jos
authors: J
authors: de Man
authors: Netherlands Translational Research Center B.V., Kloosterstraat, the Netherlands.
authors: Rogier C
authors: RC
authors: Buijsman
authors: Netherlands Translational Research Center B.V., Kloosterstraat, the Netherlands. guido.zaman@ntrc.nl.
authors: Guido J R
authors: GJ
authors: Zaman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D064127:Aurora Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D064127:Aurora Kinases; D000071221:Enhancer of Zeste Homolog 2 Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases