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Genomic imbalances associated with acquired resistance to platinum analogues
B Leyland-Jones1, L R Kelland, K R Harrap
1Department of Oncology, McGill University, Montreal, Quebec, Canada. leylandj@med.mcgill.ca
Abstract:
During the past several years, a panel of human tumor cell lines (predominantly ovarian) with acquired resistance to cisplatin, the orally bioavailable analogue JM216, and the structurally hindered analogue AMD473, has been established and characterized for underlying mechanisms of resistance. We have examined these resistant cell lines for gains and losses of DNA associated with the acquisition of resistance using the molecular cytogenetic technique of comparative genomic hybridization. Our comparison of three analogues has shown the most frequently observed changes to include amplification of 4q (5/7) and 6q (5/7), followed by amplification of 5q (3/7). We have defined four minimal common overrepresented regions, two each on 4q and 6q, which are potential loci of genes associated with platinum analogue resistance. Additional consistent abnormalities appear to be associated with cell lines sharing specific resistance mechanisms. For example, amplification of 12q was observed in the CH1 lines made respectively resistant to JM216 and AMD473 in which increased DNA repair appears to be a major mechanism of resistance for both agents. Hence, these comparative genomic hybridization studies have identified distinct chromosomal aberrations which may correlate with defined mechanisms of resistance and contain hitherto unrecognized genes that may provide targets for future therapeutic intervention.
Insights
Researchers identified DNA copy number changes in ovarian cancer cells resistant to platinum drugs like cisplatin. Amplifications on chromosomes 4q and 6q were most common, potentially harboring genes crucial for drug resistance and future cancer therapies.
Area of Science:
- Oncology
- Molecular Cytogenetics
- Cancer Genomics
Background:
- Acquired resistance to platinum-based chemotherapy, including cisplatin and its analogues (JM216, AMD473), is a significant challenge in ovarian cancer treatment.
- Understanding the genetic underpinnings of this resistance is crucial for developing more effective therapeutic strategies.
Purpose of the Study:
- To investigate DNA copy number alterations associated with acquired resistance to cisplatin and its analogues in human tumor cell lines.
- To identify specific chromosomal regions and potential genes involved in platinum analogue resistance mechanisms.
Main Methods:
- Utilized comparative genomic hybridization (CGH), a molecular cytogenetic technique, to analyze DNA gains and losses in resistant cell lines.
- Established and characterized a panel of human tumor cell lines, predominantly ovarian, with acquired resistance to cisplatin, JM216, and AMD473.
Main Results:
- Frequent DNA amplifications observed on chromosomes 4q (5/7) and 6q (5/7), followed by 5q (3/7) in resistant cell lines.
- Defined four minimal common overrepresented regions on 4q and 6q, suggesting potential loci for resistance genes.
- Observed amplification of 12q in cell lines with increased DNA repair as a resistance mechanism, linking specific aberrations to resistance pathways.
Conclusions:
- Comparative genomic hybridization studies identified distinct chromosomal aberrations correlating with platinum analogue resistance mechanisms.
- These findings highlight potential novel genes on amplified chromosomal regions that could serve as therapeutic targets for overcoming drug resistance in cancer.