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Modeling K-Ras-driven lung adenocarcinoma in mice: preclinical validation of therapeutic targets

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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.

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Acknowledgments

This work was supported by grants from the EU-Framework Program (HEALTH-F2-2010-259770/LUNGTARGET and HEALTH-2010-260791/EUROCANPLATFORM), Spanish Ministry of Economy (SAF2011-30173), and Autonomous Community of Madrid (S2011/BDM-2470/ONCOCYCLE).

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  1. Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain

    Matthias Drosten & Mariano Barbacid

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  1. Matthias Drosten
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  2. Mariano Barbacid
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Correspondence to Matthias Drosten or Mariano Barbacid.

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Drosten, M., Barbacid, M. Modeling K-Ras-driven lung adenocarcinoma in mice: preclinical validation of therapeutic targets. J Mol Med 94, 121–135 (2016). https://doi.org/10.1007/s00109-015-1360-5

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  • DOI: https://doi.org/10.1007/s00109-015-1360-5

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