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Updated: Mar 30, 2026
Detection of Lung Tumor Progression in Mice by Ultrasound Imaging
Published on: February 27, 2020
Modeling K-Ras-driven lung adenocarcinoma in mice: preclinical validation of therapeutic targets
Matthias Drosten1, Mariano Barbacid2
1Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain. mdrosten@cnio.es.
Abstract:
Lung cancer is the leading cause of cancer-related deaths worldwide, and even today, the 5-year survival rate is still below 15%. Lung adenocarcinoma is the most frequent subtype, and approximately 25% of the cases harbor activating mutations in the KRAS gene. To date, there is no effective treatment for patients carrying KRAS mutations due, at least in part, to the challenge posed by direct targeting of the KRAS oncoprotein. During the last decade, scientists have developed genetically engineered mouse models that faithfully recapitulate the natural history of the human tumors. These models have been used as a preclinical platform to validate a number of relevant downstream effectors of KRAS signaling. Targets displaying synthetic lethality with the KRAS oncoprotein have also been validated in these models. Here, we review these studies and discuss their potential value in the clinical setting. We also provide an outlook as of how to improve the significance of target validation studies in preclinical platforms.
Insights
Targeting KRAS mutations in lung cancer remains challenging. Genetically engineered mouse models are crucial preclinical tools for validating KRAS signaling effectors and synthetic lethality targets for improved lung adenocarcinoma treatments.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Lung cancer is a leading cause of cancer mortality globally, with lung adenocarcinoma being the most common subtype.
- Activating KRAS mutations occur in approximately 25% of lung adenocarcinoma cases, presenting a significant therapeutic challenge due to difficulties in directly targeting the KRAS oncoprotein.
Purpose of the Study:
- To review preclinical studies utilizing genetically engineered mouse models for validating KRAS signaling effectors and synthetic lethality targets in lung cancer.
- To discuss the clinical relevance of these validated targets and suggest improvements for preclinical target validation.
Main Methods:
- Review of studies employing genetically engineered mouse models (GEMMs) that recapitulate human lung adenocarcinoma.
- Analysis of preclinical validation of KRAS signaling downstream effectors and synthetic lethality targets within these GEMMs.
Main Results:
- GEMMs have proven effective in validating key downstream effectors of KRAS signaling.
- These models have also facilitated the validation of targets exhibiting synthetic lethality with KRAS, offering potential therapeutic avenues.
Conclusions:
- Genetically engineered mouse models are valuable preclinical platforms for identifying and validating therapeutic targets for KRAS-mutated lung cancer.
- Further refinement of preclinical target validation strategies is needed to enhance the clinical translation of findings for lung adenocarcinoma patients.
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