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Candidate genes for cross-resistance against DNA-damaging drugs
Rainer Wittig1, Michelle Nessling, Rainer D Will
1Department of Molecular Genome Analysis, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany.
Abstract:
Drug resistance of tumor cells leads to major drawbacks in the treatment of cancer. To identify candidate genes for drug resistance, we compared the expression patterns of the drug-sensitive human malignant melanoma cell line MeWo and three derived sublines with acquired resistance to the DNA-damaging agents cisplatin, etoposide, and fotemustine. Subarray analyses confirmed 57 candidate genes recovered from a genome-wide scan for differential expression. By specifically addressing cancer genes we retrieved another set of 209 candidates. Exemplary Northern blot studies indicated qualitative concordance for 110 of 135 (81.4%) data points. Whereas the etoposide-resistant line showed constant expression patterns over a period of approximately 2.5 years, the fotemustine- and cisplatin-resistant sublines exhibited considerable variability. Initially representing distinct entities, these two sublines finally converged in their expression patterns. A total of 110 genes was transiently or permanently deregulated in at least two resistant sublines. Fourteen genes displayed differential expression in all three of the sublines. We hypothesize that the variations in fotemustine and cisplatin resistance are based on progressive optimization and/or polyclonality. This, in addition to genomic alterations investigated by comparative genomic hybridization and evaluation of short-term response genes, can be used as a criterion for the selection of promising candidates. Among these are CYR61, AHCYL1, and MPP1, as well as several apoptosis-related genes, in particular STK17A and CRYAB. As MPP1 and CRYAB are also among the 14 genes differentially expressed in all three of the drug-resistant sublines, they represent the strongest candidates for resistance against DNA-damaging drugs.
Insights
Identifying genes linked to cancer drug resistance is crucial for effective treatment. This study found specific genes, like MPP1 and CRYAB, that are consistently altered in resistant melanoma cells, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Drug resistance in tumor cells poses a significant challenge in cancer therapy.
- Understanding the genetic basis of acquired resistance is essential for developing more effective treatments.
Purpose of the Study:
- To identify candidate genes associated with acquired drug resistance in human malignant melanoma.
- To compare gene expression patterns between drug-sensitive and drug-resistant melanoma cell lines.
Main Methods:
- Genome-wide gene expression analysis comparing MeWo melanoma cells with cisplatin-, etoposide-, and fotemustine-resistant sublines.
- Subarray analysis and Northern blot validation to confirm differential gene expression.
- Comparative genomic hybridization and evaluation of short-term response genes.
Main Results:
- 57 candidate genes were identified from a genome-wide scan, with an additional 209 cancer-related genes investigated.
- 110 genes showed deregulation in at least two resistant sublines; 14 genes were differentially expressed in all three.
- MPP1 and CRYAB were identified as strong candidates for resistance against DNA-damaging drugs, being deregulated in all resistant sublines.
Conclusions:
- Gene expression patterns in drug-resistant melanoma sublines can be variable but may converge over time.
- MPP1 and CRYAB are promising therapeutic targets for overcoming resistance to DNA-damaging agents in cancer.
- Progressive optimization and polyclonality may underlie variations in drug resistance acquisition.