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Single-cell sensor analyses reveal signaling programs enabling Ras-G12C drug resistance
Jason Z Zhang1,2,3, Shao-En Ong4, David Baker5,6,7
1Department of Biochemistry, University of Washington, Seattle, WA, USA. jason.zhang0428@gmail.com.
Nature Chemical Biology
|August 5, 2024
Summary
Clinical resistance to KRas-G12C inhibitors is a challenge. Single-cell analysis reveals adaptive signaling and metabolic changes in resistant cancer cells, identifying major vault protein as a key mediator.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Clinical resistance to rat sarcoma virus (Ras)-G12C inhibitors poses a significant challenge in cancer therapy.
- The immediate adaptive effects on Ras signaling at the single-cell level in response to these drugs are not well understood.
Purpose of the Study:
- To profile the activity and signaling environment of endogenous Ras at the single-cell level in response to Ras-G12C inhibitors.
- To understand the adaptive signaling and metabolic changes that contribute to drug resistance.
Main Methods:
- Utilized Ras biosensors for single-cell level profiling of endogenous Ras activity.
- Analyzed signaling and metabolic adaptations in KRas-G12C cells treated with Ras-G12C inhibitors.
Main Results:
- Identified a subpopulation of KRas-G12C cells exhibiting adaptive signaling and metabolic changes.
- Observed distinct roles for wild-type Ras at the Golgi and mutant KRas at the mitochondria in mediating resistance.
- Discovered major vault protein as a mediator of Ras activation through scaffolding signaling components and metabolite channels.
Conclusions:
- Single-cell analysis methods can reveal cellular adaptations to cancer therapies, providing insights into drug resistance mechanisms.
- Understanding these adaptations, including the role of major vault protein, is crucial for overcoming resistance to Ras-G12C inhibitors.
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