Systemic <i>Kras</i> ablation disrupts myeloid cell homeostasis in adult mice

The <i>KRAS</i> 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<sup>G12C</sup> and KRAS<sup>G12D</sup>), 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 <i>Kras</i> locus is essential for embryonic development and can sustain adult homeostasis in the absence of <i>Hras</i> and <i>Nras</i> expression. Thus, we considered of interest to interrogate the role of the <i>Kras</i> 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 <i>Kras</i> 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 <i>Kras</i> locus are primarily due to its pattern of expression rather than to the activity of its gene products.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-08-18
DOI
https://doi.org/10.1073/pnas.2512404122
Citations
3
Primary Topic
Protein Tyrosine Phosphatases
Type
article
Field-Weighted Citation Impact
2.42

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article

Systemic Kras ablation disrupts myeloid cell homeostasis in adult mice

Eduardo Caleiras, Pian Sun, Lucía Morales-Cacho, Isabel Hernández-Porras et al.
3 citations
Proceedings of the National Academy of Sciences
Protein Tyrosine Phosphatases
2.42
article

Systemic Kras ablation disrupts myeloid cell homeostasis in adult mice

Eduardo Caleiras, Pian Sun, Lucía Morales-Cacho, Isabel Hernández-Porras, Carmen Guerra, Sara Barrambana, Silvia Jiménez-Parrado, Matthias Drosten, Lucía Simón-Carrasco, Alma Dhawahir, Mariano Barbacid, Federico Virga, Francisca Mulero, Mónica Musteanu, Vasiliki Liaki, Eugenio Santos, Rafael Barrero, Elena Zamorano-Domínguez, Blanca Rosas-Pérez, Ana Galván-del-Rey
article en
3 citations

Abstract

The <i>KRAS</i> 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<sup>G12C</sup> and KRAS<sup>G12D</sup>), 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 <i>Kras</i> locus is essential for embryonic development and can sustain adult homeostasis in the absence of <i>Hras</i> and <i>Nras</i> expression. Thus, we considered of interest to interrogate the role of the <i>Kras</i> 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 <i>Kras</i> 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 <i>Kras</i> locus are primarily due to its pattern of expression rather than to the activity of its gene products.

Proceedings of the National Academy of SciencesVol. 122(34)
Roche (Switzerland) (CH), Universidad Complutense de Madrid (ES), Instituto de Salud Carlos III (ES), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (ES), Centro Nacional de Investigaciones Científicas (CU), Centro de Investigación del Cáncer (ES), Molecular Oncology (United States) (US), Centro Andaluz de Biología Molecular y Medicina Regenerativa (ES), Centro de Investigaciones Cardiovasculares (AR), Centro de Investigación Biomédica en Red de Cáncer (ES)
Ministerio de Ciencia e Innovación, Centro de Investigación Biomédica en Red de Cáncer
Openalex Percentile: Top 11%
Protein Tyrosine Phosphatases
2.42
DOIOpen Access PDFOpenAlex
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