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Updated: May 7, 2025
Author Spotlight: Developing Multiplexed Kinetic Assays for Organoid-Based Drug Response Analysis
Published on: January 5, 2024
Multiplexed mosaic tumor models reveal natural phenotypic variations in drug response within and between populations
Abstract:
Many agents that show promise in preclinical cancer models lack efficacy in patients due to patient heterogeneity that is not captured in traditional assays. To address this problem, we have developed GENEVA, a platform that measures the molecular and phenotypic consequences of drug perturbations within diverse populations of cancer cells at single-cell resolution, both in vitro and in vivo . Here, we apply GENEVA to study the KRAS G12C inhibitors, recapitulating known properties of these drugs and uncovering a previously unknown role for mitochondrial activation in cell death induced by KRAS inhibition. We demonstrate that this finding can be leveraged for the development of combination therapies with greater efficacy. Finally, we show that the application of GENEVA with in vivo mouse models revealed epithelial to mesenchymal transition (EMT) as a key mechanism for resistance to KRAS G12C inhibition.
Insights
GENEVA platform reveals mitochondrial activation drives cell death from KRAS G12C inhibitors, enabling combination therapy development. It also identified epithelial to mesenchymal transition (EMT) as a resistance mechanism in vivo.
Area of Science:
- Oncology
- Pharmacology
- Genomics
Background:
- Preclinical cancer models often fail to predict drug efficacy in patients due to unaddressed patient heterogeneity.
- Traditional assays lack the resolution to capture complex cellular responses to drug perturbations.
Purpose of the Study:
- To introduce GENEVA, a novel platform for single-cell resolution analysis of drug effects in diverse cancer cell populations.
- To investigate KRAS G12C inhibitors using GENEVA, identifying new mechanisms of action and resistance.
Main Methods:
- Development and application of the GENEVA platform for in vitro and in vivo drug perturbation studies.
- Single-cell analysis of molecular and phenotypic consequences of KRAS G12C inhibition.
- Utilizing mouse models to investigate drug resistance mechanisms.
Main Results:
- GENEVA successfully recapitulated known KRAS G12C inhibitor properties.
- Discovered a novel role for mitochondrial activation in cell death induced by KRAS inhibition.
- Identified epithelial to mesenchymal transition (EMT) as a key resistance mechanism to KRAS G12C inhibitors in vivo.
Conclusions:
- GENEVA provides a powerful tool to study drug response in heterogeneous cancer populations.
- Targeting mitochondrial activation alongside KRAS G12C inhibition may enhance therapeutic efficacy.
- Understanding EMT is crucial for overcoming resistance to KRAS G12C targeted therapies.
