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Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line

S P Cole1, G Bhardwaj, J H Gerlach

  • 1Cancer Research Laboratories, Queen's University, Kingston, Ontario, Canada.

Science (New York, N.Y.)
|December 4, 1992
PubMed

Insights

Lung cancer cells resistant to chemotherapy overexpress a novel ATP-binding cassette transporter. Gene amplification on chromosome 16 correlates with this overexpression and drug resistance, offering new therapeutic targets.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Doxorubicin-selected H69AR lung cancer cells exhibit resistance to multiple chemotherapeutic agents.
  • This resistance is not mediated by P-glycoprotein, a common multidrug resistance transporter.
  • Understanding novel resistance mechanisms is crucial for developing effective lung cancer therapies.

Purpose of the Study:

  • To identify and characterize novel genes and mechanisms conferring multidrug resistance in lung cancer.
  • To investigate the genetic basis of drug resistance in the H69AR cell line.

Main Methods:

  • Isolation of complementary DNA (cDNA) clones corresponding to overexpressed messenger RNAs (mRNAs) in H69AR cells.
  • Analysis of mRNA expression levels using hybridization techniques.
  • Gene amplification analysis via chromosomal mapping (chromosome 16, band p13.1).
  • Correlation of gene amplification and mRNA expression with drug sensitivity.

Main Results:

  • A novel mRNA (7.8–8.2 kilobases) was found to be 100- to 200-fold overexpressed in H69AR cells compared to parental H69 cells.
  • This overexpression was linked to amplification of the cognate gene on chromosome 16 at band p13.1.
  • Reversion to drug sensitivity correlated with decreased mRNA expression and loss of gene amplification.
  • The identified mRNA encodes a member of the ATP-binding cassette (ABC) transmembrane transporter superfamily.

Conclusions:

  • A novel ATP-binding cassette transporter, overexpressed due to gene amplification on chromosome 16, contributes to multidrug resistance in lung cancer.
  • This finding provides a new molecular target for overcoming chemotherapy resistance in lung cancer.

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