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High-Order Drug Combinations Are Required to Effectively Kill Colorectal Cancer Cells
Thomas Horn1, Stéphane Ferretti2, Nicolas Ebel2
1Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Abstract:
Like classical chemotherapy regimens used to treat cancer, targeted therapies will also rely upon polypharmacology, but tools are still lacking to predict which combinations of molecularly targeted drugs may be most efficacious. In this study, we used image-based proliferation and apoptosis assays in colorectal cancer cell lines to systematically investigate the efficacy of combinations of two to six drugs that target critical oncogenic pathways. Drug pairs targeting key signaling pathways resulted in synergies across a broad spectrum of genetic backgrounds but often yielded only cytostatic responses. Enhanced cytotoxicity was observed when additional processes including apoptosis and cell cycle were targeted as part of the combination. In some cases, where cell lines were resistant to paired and tripled drugs, increased expression of antiapoptotic proteins was observed, requiring a fourth-order combination to induce cytotoxicity. Our results illustrate how high-order drug combinations are needed to kill drug-resistant cancer cells, and they also show how systematic drug combination screening together with a molecular understanding of drug responses may help define optimal cocktails to overcome aggressive cancers. Cancer Res; 76(23); 6950-63. ©2016 AACR.
Insights
Targeted cancer therapies need polypharmacology. This study found high-order drug combinations, not just pairs, are essential to kill drug-resistant colorectal cancer cells by targeting multiple pathways and apoptosis.
Area of Science:
- Oncology
- Molecular Pharmacology
- Cancer Cell Biology
Background:
- Targeted cancer therapies, like chemotherapy, increasingly utilize polypharmacology.
- Predictive tools for optimal drug combinations in targeted therapy are currently lacking.
- Understanding drug synergy is crucial for overcoming cancer drug resistance.
Purpose of the Study:
- To systematically investigate the efficacy of multi-drug combinations in colorectal cancer.
- To identify optimal drug combinations targeting critical oncogenic pathways.
- To explore the role of apoptosis and cell cycle modulation in combination therapy.
Main Methods:
- Utilized image-based proliferation and apoptosis assays.
- Screened combinations of two to six molecularly targeted drugs in colorectal cancer cell lines.
- Analyzed drug responses across diverse genetic backgrounds.
Main Results:
- Paired drugs targeting key signaling pathways showed synergy but often resulted in cytostatic effects.
- Enhanced cytotoxicity was achieved by targeting additional processes like apoptosis and cell cycle.
- High-order combinations (four or more drugs) were required to induce cytotoxicity in drug-resistant cell lines exhibiting antiapoptotic protein upregulation.
Conclusions:
- High-order drug combinations are necessary to overcome drug resistance in aggressive cancers.
- Systematic drug screening combined with molecular understanding can define optimal drug cocktails.
- This approach holds promise for developing more effective treatments for challenging cancers.