Human Gene Set: TOOKER_GEMCITABINE_RESISTANCE_DN


Standard name TOOKER_GEMCITABINE_RESISTANCE_DN
Systematic name M18806
Brief description Down-regulated genes in Calu3 cells (non-small cell lung cancer, NSCLC) resistant to gemcitabine [PubChem=3461] which became up-regulated in response to bexarotene [PubChem=82146].
Full description or abstract Acquired drug resistance is a major obstacle in cancer therapy. As for many other drugs, this is also the case for gemcitabine, a nucleoside analogue with activity against non-small cell lung cancer (NSCLC). Here, we evaluate the ability of bexarotene to modulate the acquisition and maintenance of gemcitabine resistance in Calu3 NSCLC models. In the prevention model, Calu3 cells treated repeatedly with gemcitabine alone gradually developed resistance. However, with inclusion of bexarotene, the cells remained chemosensitive. RNA analysis showed a strong increase of rrm1 (ribonucleotide reductase M1) expression in the resistant cells (Calu3-GemR), a gene known to be involved in gemcitabine resistance. In addition, the expression of genes surrounding the chromosomal location of rrm1 was increased, suggesting that resistance was due to gene amplification at the chr11 p15.5 locus. Analysis of genomic DNA confirmed that the rrm1 gene copy number was increased over 10-fold. Correspondingly, fluorescence in situ hybridization analysis of metaphase chromosomes showed an intrachromosomal amplification of the rrm1 locus. In the therapeutic model, bexarotene gradually resensitized Calu3-GemR cells to gemcitabine, reaching parental drug sensitivity after 10 treatment cycles. This was associated with a loss in rrm1 amplification. Corresponding with the in vitro data, xenograft tumors generated from the resistant cells did not respond to gemcitabine but were growth inhibited when bexarotene was added to the cytotoxic agent. The data indicate that bexarotene can resensitize gemcitabine-resistant tumor cells by reversing gene amplification. This suggests that bexarotene may have clinical utility in cancers where drug resistance by gene amplification is a major obstacle to successful therapy.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 17483357   Authors: Tooker P,Yen WC,Ng SC,Negro-Vilar A,Hermann TW
Exact source Table 1S: GemR/Parental
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Source species Homo sapiens
Contributed by Jessica Robertson (MSigDB Team)
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AFFY_HG_U133
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Version history 3.0: First introduced

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