2023-10-17 19:45:11
Scientists have identified new therapeutic targets for the treatment of lung tumors in which the KRAS gene is mutated. The results open the way to finding more efficient therapies, since current ones involve the emergence of resistance mechanisms.
The research is the work of specialists from the Cancer Research Center (of the Higher Council for Scientific Research (CSIC) and the University of Salamanca) and the Institute of Biomedicine of Seville (of the CSIC, the Junta de Andalucía and the University of Seville), in Spain.
The results of this research represent the first description that the elimination of a protein called SOS1 can increase the antitumor effect in modulating the tumor microenvironment. “Specifically, we have discovered that the elimination of the SOS1 protein reduces the activity of different cell types, such as fibroblasts or macrophages, which are found in the tumor microenvironment, which in turn increases the antitumor effect,” explains Eugenio Santos. , principal investigator of the Cancer Research Center (CIC) and the Cancer Network Biomedical Research Center (CIBERONC) in Spain.
Work has focused on the effect of SOS1/2 deletion on the onset and progression of KRAS-mutated lung adenocarcinoma. “SOS1 and SOS2 may be potential therapeutic targets in other tumor types with the same mutation, such as, for example, pancreatic cancer and colorectal cancer. Therefore, this work opens new working hypotheses for these types of tumors,” indicates Fernando Calvo Baltanás, researcher in the Neural Stem Cell Physiopathology Laboratory at the Institute of Biomedicine of Seville (IBiS) and professor at the Department of Medical Physiology and Biophysics of the University of Seville.
Artistic recreation of cancer cell. (Image: Amazings/NCYT)
SOS1 inhibitors
In the last three years, at least three pharmaceutical companies have developed specific inhibitors for the SOS1 protein, and some of them are even in phase I clinical trials. In this context, the research group led by Santos has the genetically modified research mouse models that have the mutation that inhibits the expression of the SOS1 protein, and one of its main lines of research is the study of the function of SOS1 in physiological and pathological conditions. This work has shown in murine models that eliminating SOS1 expression has an antitumor effect in certain types of lung adenocarcinoma. If clinical trials progress satisfactorily, these compounds could be evaluated in patients suffering from this same pathology.
Until a few years ago, the established dogma was that the treatment of tumors with mutations in the RAS oncogene focused on the search for drugs that act directly against RAS or against proteins that are activated by RAS. In this context SOS1 and SOS2 are not in this position, but rather they activate RAS, so initially inhibiting SOS1/2 should not have a priori any antitumor effect.
Although the present work is focused on lung adenocarcinoma, other works by the group have also shown that SOS1 is essential for the development of chronic myeloid leukemia and chemically induced skin tumors, suggesting that SOS1 may constitute a valid therapeutic target. for a wide variety of different RAS-dependent tumors.
To demonstrate this hypothesis, various methodologies have been used in this work, including the use of murine models and genetically modified cell lines, the use of drugs, the evaluation of different physiological parameters (oxygen saturation, electrocardiogram…), advanced imaging techniques. such as computerized microtomography, molecular biology techniques such as ELISA, real-time quantitative PCR or Western-blot or immunohistochemical and histology techniques, among others.
The study is titled “Critical requirement of SOS1 for tumor development and microenvironment modulation in KRASG12D-driven lung adenocarcinoma.” And it has been published in the academic journal Nature Communications. (Source: IBiS / CIC / CSIC)
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