Systemic <i>Kras</i> ablation disrupts myeloid cell homeostasis in adult mice
Abstract
The KRAS oncogene has been associated with many types of cancer, including pancreatic, lung, and colorectal. For decades, its gene products were thought to be undruggable. However, during the last decade, a large battery of KRAS inhibitors selective against specific mutations (KRAS G12C and KRAS G12D ), panKRAS inhibitors active against all KRAS isoforms, or even panRAS inhibitors, capable of inhibiting the three members of the RAS family, have been developed. In mice, the Kras locus is essential for embryonic development and can sustain adult homeostasis in the absence of Hras and Nras expression. Thus, we considered of interest to interrogate the role of the Kras locus in an experimental system to generate potentially relevant information regarding the use of panKRAS or panRAS inhibitors in the clinic. Here, we report that systemic ablation of Kras expression in adult mice does not induce significant changes in overall survival, body weight, glucose levels, metabolic profile, or heart function. In contrast, flow cytometry and histopathological analyses of organs such as blood, bone marrow, and spleen showed a significant increase of the myeloid lineage leading to myelomonocytic metaplasia. In this context, replacement of the KRAS isoforms by HRAS is sufficient to maintain adult homeostasis, suggesting that the unique properties of the Kras locus are primarily due to its pattern of expression rather than to the activity of its gene products.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Elena Zamorano-Dominguez
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Lucia Morales-Cacho
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Rebeca Barrero
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Silvia Jiménez-Parrado
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Alma Dhawahir
Global Pharma Strategy, F. Hoffmann-La Roche Ltd
Isabel Hernández-Porras
Experimental Oncology Group, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas
Lucía Simón-Carrasco
Molecular Oncology and Targeted Therapies Group, Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide
Sara Barrambana
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Pian Sun
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Ana Galván-del-Rey
Experimental Oncology Group, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas
Blanca Rosas-Perez
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Vasiliki Liaki
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Matthias Drosten
Centro de Investigación Biomédica en Red Cancer (CIBERONC)
Monica Musteanu
Federico Virga
Experimental Oncology Group, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas
Eugenio Santos
Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III
Francisca Mulero
Molecular Imaging Unit, Biotechnology Program, Centro Nacional de Investigaciones Oncológicas
Eduardo Caleiras
Histopathology Unit, Biotechnology Program, Centro Nacional de Investigaciones Oncológicas
Carmen Guerra
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Mariano Barbacid