STANDARD_NAME HANN_RESISTANCE_TO_BCL2_INHIBITOR_UP SYSTEMATIC_NAME M11749 COLLECTION C2:CGP MSIGDB_URL https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/HANN_RESISTANCE_TO_BCL2_INHIBITOR_UP NAMESPACE HUMAN_GENE_SYMBOL DESCRIPTION_BRIEF Genes up-regulated in SCLC (small cell lung cancer) cells with acquired resistance to ABT-737 [PubChem=11228183], an inhibitor of the BCL2 [GeneID=596] family proteins. DESCRIPTION_FULL Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. We compared primary SCLC xenografts prepared from de novo human tumors with standard cell line-based xenografts in the evaluation of a novel and highly potent small molecule inhibitor of Bcl-2, ABT-737. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines. In contrast, only one of three primary xenograft SCLC tumors showed significant growth inhibition with ABT-737. Explanations for this apparent dichotomy may include relatively low expression of Bcl-2 in the primary xenografts or inherent differences in the model systems. The addition of etoposide to ABT-737 in the primary xenografts resulted in significant decreases in tumor growth, underscoring the clinical potential of ABT-737 in combination therapy. To identify factors that may contribute to resistance to ABT-737 and related inhibitors, we isolated resistant derivatives of an initially sensitive cell line-based xenograft. Acquired resistance in this model was associated with decreases in the expression of the primary target Bcl-2, of proapoptotic partners of Bcl-2 (Bax and Bim), and of Bcl-2:Bim heterodimers. Expression profiling reveals 85 candidate genes demonstrating consistent changes in gene expression with acquired resistance. Taken together, these data have specific implications for the clinical development of Bcl-2 inhibitors for SCLC and broader implications for the testing of novel anticancer strategies in relevant preclinical models. PMID 18381439 GEOID GSE10003 AUTHORS Hann CL,Daniel VC,Sugar EA,Dobromilskaya I,Murphy SC,Cope L,Lin X,Hierman JS,Wilburn DL,Watkins DN,Rudin CM CONTRIBUTOR Jessica Robertson CONTRIBUTOR_ORG MSigDB Team EXACT_SOURCE Table 1S: Increased in H187-63 AR FILTERED_BY_SIMILARITY EXTERNAL_NAMES_FOR_SIMILAR_TERMS EXTERNAL_DETAILS_URL SOURCE_MEMBERS ATP8B2,BRSK2,C10orf38,CD81,D4S234E,DCX,EEF1A2,ELAVL3,FLJ20647,FLNC,FSCN1,GNG2,GPX2,HBA1,HOXB9,IGSF9,ITM2C,KCNK16,KCNT1,MT1F,MT1G,MXRA5,NPTX2,OLFM1,PCSK1N,PNMA2,PPP2R2C,RTN1,SCD,SPRR2F,SST,STMN2,TAGLN2,TNFRSF8,VCX,ZNF91 GENE_SYMBOLS ATP8B2,BRSK2,FAM171A1,CD81,NSG1,DCX,EEF1A2,ELAVL3,MCUB,FLNC,FSCN1,GNG2,GPX2,HBA1,HOXB9,IGSF9,ITM2C,KCNK16,KCNT1,MT1F,MT1G,MXRA5,NPTX2,OLFM1,PCSK1N,PNMA2,PPP2R2C,RTN1,SCD,SPRR2F,SST,STMN2,TAGLN2,TNFRSF8,VCX,ZNF91 FOUNDER_NAMES