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

Matthias Drosten; Mariano Barbacid

doi:10.1007/s00109-015-1360-5

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

J Mol Med (Berl). 2016 Feb;94(2):121-35. doi: 10.1007/s00109-015-1360-5. Epub 2015 Nov 3.

Authors

Matthias Drosten¹, Mariano Barbacid²

Affiliations

¹ Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain. [email protected].
² Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain. [email protected].

PMID: 26526121
DOI: 10.1007/s00109-015-1360-5

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.

Keywords: GEMMs; Mouse models; Target validation; Therapeutic strategies.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Adenocarcinoma / drug therapy
Adenocarcinoma / genetics*
Adenocarcinoma / metabolism*
Adenocarcinoma / pathology
Adenocarcinoma of Lung
Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Cell Cycle / drug effects
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Disease Models, Animal
Drug Evaluation, Preclinical
Drug Resistance, Neoplasm
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism*
Lung Neoplasms / pathology
MAP Kinase Signaling System
Mice
Molecular Targeted Therapy
Mutation
Neoplasm Metastasis
Oncogenes
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors
Proto-Oncogene Proteins p21(ras) / genetics*
Proto-Oncogene Proteins p21(ras) / metabolism*
Signal Transduction / drug effects

Substances

Antineoplastic Agents
Biomarkers, Tumor
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins p21(ras)