STANDARD_NAME	NUNODA_RESPONSE_TO_DASATINIB_IMATINIB_UP
SYSTEMATIC_NAME	M15510
COLLECTION	C2:CGP
MSIGDB_URL	https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/NUNODA_RESPONSE_TO_DASATINIB_IMATINIB_UP
NAMESPACE	HUMAN_GENE_SYMBOL
DESCRIPTION_BRIEF	Genes up-regulated in K562 cells (bone marrow) after treatment with dasatinib [PubChem=3062316] or imatinib [PubChem=5291].
DESCRIPTION_FULL	Dasatinib is an ATP-competitive, multi-targeted SRC and ABL kinase inhibitor that can bind BCR-ABL in both the active and inactive conformations. From a clinical standpoint, dasatinib is particularly attractive because it has been shown to induce hematologic and cytogenetic responses in imatinib-resistant chronic myeloid leukemia patients. The fact because the combination of imatinib and dasatinib shows the additive/synergistic growth inhibition on wild-type p210 BCR-ABL-expressing cells, we reasoned that these ABL kinase inhibitors might induce the different molecular pathways. To address this question, we used DNA microarrays to identify genes whose transcription was altered by imatinib and dasatinib. K562 cells were cultured with imatinib or dasatinib for 16 h, and gene expression data were obtained from three independent microarray hybridizations. Almost all of the imatinib- and dasatinib-responsive genes appeared to be similarly increased or decreased in K562 cells; however, small subsets of genes were identified as selectively altered expression by either imatinib or dasatinib. The distinct genes that are selectively modulated by dasatinib are cyclin-dependent kinase 2 (CDK2) and CDK8, which had a maximal reduction of <5-fold in microarray screen. To assess the functional importance of dasatinib regulated genes, we used RNA interference to determine whether reduction of CDK2 and CDK8 affected the growth inhibition. K562 and TF-1BCR-ABL cells, pretreated with CDK2 or CDK8 small interfering RNA, showed additive growth inhibition with imatinib, but not with dasatinib. These findings demonstrate that the additive/synergistic growth inhibition by imatinib and dasatinib may be mediated in part by CDK2 and CDK8.
PMID	17213809
GEOID	GSE2810
AUTHORS	Nunoda K,Tauchi T,Takaku T,Okabe S,Akahane D,Sashida G,Ohyashiki JH,Ohyashiki K
CONTRIBUTOR	Arthur Liberzon
CONTRIBUTOR_ORG	MSigDB Team
EXACT_SOURCE	Fig 3, 4
FILTERED_BY_SIMILARITY	
EXTERNAL_NAMES_FOR_SIMILAR_TERMS	
EXTERNAL_DETAILS_URL	
SOURCE_MEMBERS	BCL2,CASP6,CASP7,CCNA2,CCND2,CCND3,CCNE1,CDC25A,CDC25B,CDC25C,CDC2L5,CDK4,CDK5R1,CDK6,CDK8,CDK9,E2F3,E2F4,E2F5,GADD45B,MCL1,MYC,NFKB1,NFKBIA,RAD50,RAD51,STAT3,XRCC3,XRCC4
GENE_SYMBOLS	BCL2,CASP6,CASP7,CCNA2,CCND2,CCND3,CCNE1,CDC25A,CDC25B,CDC25C,CDK13,CDK4,CDK5R1,CDK6,CDK8,CDK9,E2F3,E2F4,E2F5,GADD45B,MCL1,MYC,NFKB1,NFKBIA,RAD50,RAD51,STAT3,XRCC3,XRCC4
FOUNDER_NAMES