Human Gene Set: HANN_RESISTANCE_TO_BCL2_INHIBITOR_DN


Standard name HANN_RESISTANCE_TO_BCL2_INHIBITOR_DN
Systematic name M4339
Brief description Genes down-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.
Full description or abstract 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.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 18381439   Authors: Hann CL,Daniel VC,Sugar EA,Dobromilskaya I,Murphy SC,Cope L,Lin X,Hierman JS,Wilburn DL,Watkins DN,Rudin CM
Exact source Table 1S: Decreased in H187-63AR
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Source species Homo sapiens
Contributed by Jessica Robertson (MSigDB Team)
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identifier namespace		 HUMAN_GENE_SYMBOL
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Version history 3.0: First introduced

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