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Synthetic lethal screening with small-molecule inhibitors provides a pathway to rational combination therapies for
Devin G Roller1, Mark Axelrod, Brian J Capaldo
1Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Jordan Hall Rm 2-16, Box 800734, 1300 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
Abstract:
Recent data show that extracellular signals are transmitted through a network of proteins rather than hierarchical signaling pathways, suggesting that the inhibition of a single component of a canonical pathway is insufficient for the treatment of cancer. The biologic outcome of signaling through a network is inherently more robust and resistant to inhibition of a single network component. In this study, we conducted a functional chemical genetic screen to identify novel interactions between signaling inhibitors that would not be predicted on the basis of our current understanding of signaling networks. We screened over 300 drug combinations in nine melanoma cell lines and have identified pairs of compounds that show synergistic cytotoxicity. The synergistic cytotoxicities identified did not correlate with the known RAS and BRAF mutational status of the melanoma cell lines. Among the most robust results was synergy between sorafenib, a multikinase inhibitor with activity against RAF, and diclofenac, a nonsteroidal anti-inflammatory drug (NSAID). Drug substitution experiments using the NSAIDs celecoxib and ibuprofen or the MAP-ERK kinase inhibitor PD325901 and the RAF inhibitor RAF265 suggest that inhibition of COX and mitogen-activated protein kinase signaling are targets for the synergistic cytotoxicity of sorafenib and diclofenac. Cotreatment with sorafenib and diclofenac interrupts a positive feedback signaling loop involving extracellular signal-regulated kinase, cellular phospholipase A2, and COX. Genome-wide expression profiling shows synergy-specific downregulation of survival-related genes. This study has uncovered novel functional drug combinations and suggests that the underlying signaling networks that control responses to targeted agents can vary substantially, depending on unexplored components of the cell genotype.
Insights
Targeting cancer networks requires novel drug combinations. Researchers found synergistic effects between sorafenib and diclofenac, highlighting new therapeutic strategies beyond single-pathway inhibition for melanoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Extracellular signals are transmitted via protein networks, not just hierarchical pathways.
- Inhibiting single components of canonical pathways is often insufficient for effective cancer treatment.
- Network signaling provides robustness, making it resistant to single-target inhibition.
Purpose of the Study:
- To identify novel synergistic interactions between signaling inhibitors using a functional chemical genetic screen.
- To discover drug combinations not predictable by current understanding of signaling networks.
- To explore new therapeutic strategies for melanoma by targeting complex signaling networks.
Main Methods:
- Conducted a functional chemical genetic screen of over 300 drug combinations in nine melanoma cell lines.
- Identified synergistic cytotoxicity between pairs of compounds.
- Performed drug substitution experiments and genome-wide expression profiling to elucidate mechanisms.
Main Results:
- Identified synergistic cytotoxicity between sorafenib (a multikinase inhibitor) and diclofenac (a nonsteroidal anti-inflammatory drug).
- Synergistic effects were independent of known RAS and BRAF mutational status.
- Inhibition of COX and mitogen-activated protein kinase signaling pathways were identified as key targets.
- Cotreatment interrupted a positive feedback loop involving extracellular signal-regulated kinase, cellular phospholipase A2, and COX.
- Genome-wide expression profiling revealed synergy-specific downregulation of survival-related genes.
Conclusions:
- Novel functional drug combinations can be uncovered by screening against complex signaling networks.
- The combination of sorafenib and diclofenac demonstrates significant synergistic cytotoxicity in melanoma.
- Understanding underlying signaling networks, including unexplored components, is crucial for developing effective targeted therapies.