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Systemic Kras ablation disrupts myeloid cell homeostasis in adult mice
Elena Zamorano-Dominguez1,2, Lucía Morales-Cacho1, Rebeca Barrero1
1Experimental Oncology Group, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain.
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 (KRASG12C and KRASG12D), 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.
Insights
Ablating Kras in adult mice did not affect survival but caused myeloid lineage expansion. HRAS can compensate for Kras, suggesting Kras
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The KRAS oncogene is implicated in various cancers, with KRAS proteins historically considered undruggable.
- Recent advancements include the development of selective KRAS inhibitors (e.g., for KRASG12C, KRASG12D) and broader panKRAS/panRAS inhibitors.
- The Kras locus is vital for embryonic development and can support adult homeostasis when Hras and Nras are absent.
Purpose of the Study:
- To investigate the role of the Kras locus in adult mice.
- To generate data relevant to the clinical use of panKRAS or panRAS inhibitors.
- To understand Kras's contribution to homeostasis and potential functional redundancy with HRAS and NRAS.
Main Methods:
- Systemic ablation of Kras expression in adult mice.
- Assessment of overall survival, body weight, glucose levels, metabolic profile, and heart function.
- Flow cytometry and histopathological analyses of blood, bone marrow, and spleen.
Main Results:
- Systemic Kras ablation in adult mice did not significantly alter survival, body weight, or metabolic/cardiac function.
- Significant myeloid lineage expansion and myelomonocytic metaplasia were observed in blood, bone marrow, and spleen.
- HRAS isoform replacement was sufficient to maintain adult homeostasis, indicating Kras's expression pattern is key.
Conclusions:
- Kras is not essential for adult mouse homeostasis when HRAS can compensate.
- The Kras locus's primary importance may lie in its expression pattern rather than its gene products' activity.
- Findings inform the potential clinical application of panKRAS and panRAS inhibitors.
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