Genetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cells

Area of Science:

• Genomics
• Cancer Biology
• Molecular Oncology

Background:

• The multidrug resistant (MDR) phenotype is often linked to ATP-binding cassette (ABC) transporters, like P-glycoprotein (ABCB1).
• Previous research suggests MDR may involve more than a single gene.
• Understanding the genetic basis of MDR is crucial for developing effective cancer therapies.

Purpose of the Study:

• To identify genetic factors contributing to the emergence of MDR.
• To investigate the role of gene expression and copy number alterations in MDR development.
• To analyze the dynamic genomic changes associated with increasing drug resistance.

Main Methods:

• Integrative genomics analysis of ovarian carcinoma cell line SKOV3 and its MDR derivatives (SKVCRs).
• Comparative gene expression analysis.
• Whole genome tiling-path array comparative genomic hybridization (CGH).
• Functional annotation and pathway analysis.

Main Results:

• Increased drug resistance correlated with the activation of a network of genes beyond ABCB1.
• Many activated genes are associated with the extracellular matrix, tumor invasion, and cell proliferation.
• Gene dosage changes, particularly segmental DNA alterations, were key to activating overexpressed genes.
• A novel amplicon at 16p13 (encompassing ABCC1 and ABCC6) emerged and declined, replaced by an amplicon at 7q21.12 (harboring ABCB1) in highly resistant lines.

Conclusions:

• The evolution of the MDR phenotype is a dynamic, multi-genic process.
• Multiple genes, including a succession of ABC transporter genes and those synergistic with ABCB1, are activated during drug resistance escalation.
• Genomic alterations, such as amplifications and deletions, play a significant role in the dynamic emergence of MDR.