KRAS is one of the first oncogenes discovered and the one most frequently found to be mutated in humans; and is involved in a quarter of the tumors. For this reason, the development of drugs that inhibit its action is a very active field of research, but in which it is difficult to achieve results. However, the US Food and Drug Administration (FDA) just approved the first compound, known as sotorasib.
The KRAS oncogene orders the synthesis of two proteins, KRAS4A and KRAS4B, whose levels can vary depending on the organ and the stage of the embryonic development. When KRAS acquires a mutation, the two proteins – called isoforms because they are the product of the same gene – are activated, with KRAS4B being the one most expressed in tumors and, therefore, the one on which scientific studies have focused the most. to develop strategies that allow their inhibition.
KRAS is the most frequently mutated oncogene in humans. The development of drugs that inhibit their action is a very active field, but in which it is difficult to achieve results
However, researchers from the Experimental Oncology Group of the National Cancer Research Center (CNIO), led by Mariano Barbacid, decided to study each isoform separately in order to understand the functions they perform individually. “The biological relevance of the expression of the two isoforms has intrigued specialists for decades,” explain the authors of this work, published in the scientific journal PNAS.
Implications of KRAS in embryonic development
This research has revealed that the mutated form of KRAS4A (KRAS4AG12V) is also oncogenic, and with higher activity than KRAS4B, which the authors have described as “a surprise.”
“We found that the KRAS4AG12V protein alone, in the absence of KRAS4B, is capable of promoting tumor formation in the lung and inducing metastasis in 20% of the cases ”, they write. Therefore, “these results suggest that the treatments against the KRAS oncogene will only be effective if it acts on both isoforms”, the experts add.
We found that the KRAS4AG12V protein alone, in the absence of KRAS4B, is capable of promoting tumor formation in the lung and inducing metastasis in 20% of cases. These results suggest that treatments against the KRAS oncogene will only be effective if both isoforms are acted upon.
To reach that conclusion, the researchers designed two genetically modified mouse models that lack KRAS4B, and express only the KRAS4A protein, either in its healthy form or with the mutation.
Finally, the work analyzes the role of both isoforms in embryonic development and reveals that the KRAS4B isoform “is essential in postnatal development, since its absence causes important cardiac abnormalities that prevent the growth of the mouse ”.
Salmon et al. “KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform”. PNAS, 2021. DOI: 10.1073 / pnas.2023112118
Rights: Creative Commons.