Mapping the Pathways of Resistance to Targeted Therapies
1Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina. kris.wood@duke.edu.
Abstract:
Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies. Through the use of complementary experimental approaches, investigators have revealed that cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic, or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation of signaling pathways that, when co-opted, enable cancer cells to survive drug treatments. Recently developed methods enable the direct and scalable identification of the signaling pathways capable of driving resistance in specific contexts. Using these methods, novel pathways of resistance to clinically approved drugs have been identified and validated. By combining systematic resistance pathway mapping methods with studies revealing biomarkers of specific resistance pathways and pharmacologic approaches to block these pathways, it may be possible to rationally construct drug combinations that yield more penetrant and lasting responses in patients.
Insights
Cancer cells develop resistance to targeted therapies through genetic or environmental changes, activating survival pathways. Identifying these resistance pathways can help create combination therapies for longer-lasting patient responses.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Resistance to targeted anticancer therapies limits treatment efficacy.
- Cancer cells acquire resistance via genetic, epigenetic, or microenvironmental changes.
- These alterations often activate specific signaling pathways enabling survival.
Purpose of the Study:
- To identify and validate novel resistance pathways to targeted anticancer drugs.
- To explore methods for scalable identification of resistance-driving signaling pathways.
- To lay the groundwork for rationally designed combination therapies.
Main Methods:
- Employed complementary experimental approaches to investigate resistance mechanisms.
- Utilized recently developed methods for direct and scalable identification of resistance pathways.
- Validated identified resistance pathways in relevant cancer contexts.
Main Results:
- Revealed diverse mechanisms of resistance, including adaptation and selection.
- Identified and validated novel signaling pathways driving resistance to approved drugs.
- Demonstrated the link between specific alterations and pathway activation.
Conclusions:
- Understanding resistance pathways is crucial for overcoming treatment limitations.
- Systematic mapping of resistance pathways can inform biomarker discovery.
- Combining pathway mapping, biomarker identification, and blockade strategies may yield more durable responses.
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