New research carried out by scientists from the Cancer Research Center (CSIC-University of Salamanca) and the Institute of Biomedicine of Seville (CSIC-Junta de Andalucía-Universidad de Sevilla) has shown that suppressing the SOS1 and SOS2 genes has a antitumor effect in lung cancer with KRAS mutation. This finding is of great relevance, since this type of tumors become resistant to available therapies and discovering new therapeutic targets will allow the development of new, more effective treatments against lung cancer.
The study has been published in the journal Nature communications and has been led in the IBiS by the Dr. Fernando Calvo Baltanásresearcher in the Laboratory of Neural Stem Cell Pathophysiology at the IBiS and professor belonging to the Department of Medical Physiology and Biophysics of the University of Seville, and at the CIC for the Dr. Eugenio Santos. Their results represent the first description that the elimination of a protein called SOS1 can increase the antitumor effect by 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,” explained the Dr. Santos, principal investigator of the Cancer Research Center (CIC) and CIBERONC.
Relationship between cancer, RAS proteins and SOS1 and SOS2 genes
Las Ras proteins They are responsible for regulating a wide variety of cellular processes, such as proliferation, differentiation, cell adhesion and migration, or apoptosis (or controlled cell death), among others. By intervening in such complex processes, its mutation is related to the appearance and virulence of malignant tumors.
“SOS1 (and SOS2) are therapeutic targets for patients with lung adenocarcinoma induced by the KRASG12D mutation, but they may have antitumor effects in other types of solid tumors that carry the same mutation”
The function of the SOS1 and SOS2 genes is, among other things, to activate the RAS protein. Its role, as has been proven, may be key in the uncontrolled activation of RAS, which can lead to the development of cancer. “In the 1980s, doctors Eugenio Santos, also the author of this work, and Mariano Barbacid described the RAS genes as the first human oncogenes (i.e. a mutation in these genes causes cancer),” explains Dr. Calvo Baltanás. “When these genes mutate, they become more active, and, therefore, the cells of a tissue proliferate more, thus generating the tumor.”
The researcher adds that, after this discovery, most of the efforts in the field of oncology were dedicated to the search for treatments that directly inhibit RAS as it is a specific therapeutic target. “However, this search was fruitless until very few years ago. Recently, representing a scientific-medical milestone, a series of drugs were presented that acted against specific RAS mutations. These have already been tested on humans and have shown great efficiency in increasing patient survival. Unfortunately, the prolonged use of these compounds has generated resistance mechanismsreducing its response and, therefore, the search for new therapeutic targets to overcome these mechanisms is essential.”
If the SOS1 and SOS2 proteins act as activators of RAS, the researchers decided to investigate what happened if they inhibited their action. “From the laboratory, our starting hypothesis was that due to its crucial role in regulating the main signaling pathway that controls cell proliferation [conocida como ruta EGFR-RAS-MAPK], the control of these proteins could modulate, in turn, the proliferation of tumor cells, in this case lung cancer. Mutations in this signaling pathway that consequently develop lung adenocarcinoma They are present in more than half of the cases of this type of cancer. It could be expected, as we have shown here, that the inhibition or elimination of SOS1 and SOS2 would result in a lower activity of the RAS proteins and, therefore, a reduction in cell proliferation,” confirms the doctor.
Deleting SOS1 reduces tumor size and progression
But what happens when we eliminate SOS1 and SOS2 from the equation? Dr. Calvo continues his explanations in this regard: “In this work we have found several very encouraging results from a therapeutic point of view.” “First of all, eliminating these genes (especially SOS1) very significantly reduces the appearance of the tumor. However, although this is of great importance from the point of view of knowing its biology, it is not what happens in clinical practice. “That is, here we have been able to see what happens if we eliminate SOS1 and SOS2 before the tumor appears, and as I say, it is not what happens in real life.”
In this way, the researcher shows that there is a big difference between a laboratory environment and a real one, in which the person does not think about preventing a hypothetical tumor, but rather about treating the appearance of one: “We wanted to know whether to eliminate these proteins reduced an already formed tumor, which is what happens on a daily basis with patients. And our results show that eliminating SOS1 reduces its size very strikingly,” he says.
“Finally, we have discovered another antitumor function, not previously described for SOS1. And one of the characteristics that favors a tumor to progress is the action of certain cell types that are found surrounding the tumor.” This factor described by Dr. Calvo is called tumor microenvironment and refers to the cellular niche that surrounds the cancer. “Our results prove that the elimination of SOS1 reduces the activity of the cells that are in this tumor environment, and as a result tumor progression is reduced. “Potentially, and we are now dedicating our efforts to exploring this pathway, deletion of SOS1 could have a microenvironment-reducing effect on a large number of solid tumors other than lung cancer.”
A way to improve the effectiveness of cancer treatments
In general, discovering, refining and adapting oncology treatments for use in clinical practice takes a long time. However, as a whole, RAS and its oncogenic role have been studied for decades, which currently places it in a privileged position in the fight against cancer. “This therapeutic target is not only a therapy that could be used in the future,” comments the expert. “It is already a reality. At this time there are clinical trials in patients with other types of solid tumors, such as those of pancreaswhich present a type of mutation in RAS (KRASG12C), where inhibition of SOS1 shows antitumor effects.”
“Our work demonstrates,” continues the scientist, “that SOS1 (and SOS2) are therapeutic targets for patients with lung adenocarcinoma induced by KRASG12D mutation, although our hypothesis is that SOS1 and SOS2 may have antitumor effects in other types of solid tumors, carrying the same mutation and even other mutations other than the EGFR-RAS-MAPK pathway. This would mean the use of drugs aimed at controlling these two genes not only for lung cancer, but for many other types.”
According to Dr. Calvo, at this moment there are at least three pharmaceutical companies that have already developed specific drugs against SOS1 and their availability could be ready. within five to 10 years. “Of these inhibitors, one of them is already in Phase I clinical trials with patients, so its use – if the trials progress as planned – in humans could be ready in about five or ten years. The greatest barrier that arises with the use of drugs that inhibit RAS proteins is the development of resistance mechanisms,” he explains, referring again to the resistance caused by the use of this type of medication for long periods of time. “This is why, as we have done in this study with SOS1, identifying new therapeutic targets that increase the tumor efficacy of compounds already approved for use in patients is essential.”
Fuentes: Institute of Biomedicine of Seville (IBiS) and Cancer Research Center (CIC)