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Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines
Pallavi Sachdev1, Roy Ronen2, Janusz Dutkowski2
1Eisai Inc., Nutley, NJ 07110, USA.
Abstract:
Eribulin, a natural product-based microtubule targeting agent with cytotoxic and noncytotoxic mechanisms, is FDA approved for certain patients with advanced breast cancer and liposarcoma. To investigate the feasibility of developing drug-specific predictive biomarkers, we quantified antiproliferative activities of eribulin versus paclitaxel and vinorelbine against 100 human cancer cell lines from the Cancer Cell Line Encyclopedia, and correlated results with publicly available databases to identify genes and pathways associated with eribulin response, either uniquely or shared with paclitaxel or vinorelbine. Mean expression ratios of 11,985 genes between the most and least sensitive cell line quartiles were sorted by p-values and drug overlaps, yielding 52, 29 and 80 genes uniquely associated with eribulin, paclitaxel and vinorelbine, respectively. Further restriction to minimum 2-fold ratios followed by reintroducing data from the middle two quartiles identified 9 and 13 drug-specific unique fingerprint genes for eribulin and vinorelbine, respectively; surprisingly, no gene met all criteria for paclitaxel. Interactome and Reactome pathway analyses showed that unique fingerprint genes of both drugs were primarily associated with cellular signaling, not microtubule-related pathways, although considerable differences existed in individual pathways identified. Finally, four-gene (C5ORF38, DAAM1, IRX2, CD70) and five-gene (EPHA2, NGEF, SEPTIN10, TRIP10, VSIG10) multivariate regression models for eribulin and vinorelbine showed high statistical correlation with drug-specific responses across the 100 cell lines and accurately calculated predicted mean IC50s for the most and least sensitive cell line quartiles as surrogates for responders and nonresponders, respectively. Collectively, these results provide a foundation for developing drug-specific predictive biomarkers for eribulin and vinorelbine.
Insights
Researchers identified unique gene "fingerprints" for eribulin and vinorelbine, paving the way for predictive biomarkers. These findings help personalize cancer treatment by identifying which patients will best respond to these microtubule-targeting agents.
Area of Science:
- Oncology
- Pharmacogenomics
- Molecular Biology
Background:
- Eribulin is an FDA-approved microtubule targeting agent for advanced breast cancer and liposarcoma.
- Developing drug-specific predictive biomarkers is crucial for optimizing treatment efficacy.
- Understanding differential drug responses requires comprehensive gene expression analysis.
Purpose of the Study:
- To identify genes and pathways associated with eribulin response, distinct from paclitaxel and vinorelbine.
- To investigate the feasibility of developing drug-specific predictive biomarkers for eribulin and vinorelbine.
- To correlate gene expression profiles with antiproliferative activity across a panel of cancer cell lines.
Main Methods:
- Quantified antiproliferative activity of eribulin, paclitaxel, and vinorelbine against 100 human cancer cell lines.
- Correlated drug response data with public gene expression databases.
- Performed interactome and Reactome pathway analyses on identified gene sets.
Main Results:
- Identified unique "fingerprint" genes for eribulin (9 genes) and vinorelbine (13 genes), but not for paclitaxel.
- Found that unique fingerprint genes were associated with cellular signaling pathways, not microtubule-related pathways.
- Developed multivariate regression models with high statistical correlation for predicting drug-specific responses.
Conclusions:
- Established a foundation for developing drug-specific predictive biomarkers for eribulin and vinorelbine.
- Demonstrated the potential of gene expression profiling to predict patient response to microtubule-targeting agents.
- Highlighted the distinct molecular mechanisms underlying responses to these chemotherapeutics.