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.