An international review published in the journal "Molecular Cancer" identifies the SOS1 protein as a central piece in new therapeutic strategies against tumors dependent on the RAS pathway, one of the most altered signaling routes in human cancer.
The study, carried out by a national consortium involving the Center for Cancer Research (CSIC, USAL, FICUS) and the Institute of Biomedicine of Seville, compiles nearly thirty years of basic and translational research on SOS1, and evaluates for the first time in an organized manner the different inhibitors and degraders of this protein that are being tested in patient-derived models.
"This review analyzes the main advances of the last decade on the SOS1 protein as a therapeutic target in a wide variety of human models, both preclinical and clinical. This set of results will be key to driving the development of future personalized therapies in numerous tumor processes dependent on RAS oncogenes," highlighted Fernando Calvo, a researcher at the Institute of Biomedicine of Seville.
RAS proteins function as small molecular switches that control cell proliferation, survival, and migration signals, and are mutated in a very high proportion of neoplasms such as lung, colon, or pancreatic cancer. For decades, RAS was considered an "undruggable" target, until the advent of the first drugs targeting the KRAS G12C mutation, which have brought about a shift in therapeutic approach, although they have also revealed the rapid emergence of resistance.
In this scenario, the review highlights the relevance of SOS1, a protein that helps activate RAS by facilitating the transition from its inactive state to its active form, and which remains critical even in numerous tumors with oncogenic mutations in RAS. This dependence makes SOS1 a particularly interesting target for the design of drugs capable of attenuating tumor signaling and enhancing the efficacy of existing therapies.
The article details different families of SOS1 inhibitors, such as BAY-293, BI-3406, or MRTX0902, and explains in which types of tumors and specific mutations they show greater activity, as well as the most promising combinations with other targeted agents, for example, KRAS G12C, MEK, or epidermal growth factor receptor EGFR inhibitors.
In models derived from patients, it has been observed that these combinations induce more intense anti-tumor responses, delay the onset of resistance, and can even reverse acquired resistance to other molecules.
The review also highlights a new generation of compounds called PROTACs, designed to degrade the SOS1 protein rather than simply blocking its activity. These degraders achieve more prolonged effects on the RAS-MAPK signaling pathway and show superior anti-tumor activity compared to conventional inhibitors in various preclinical models.
From a clinical perspective, the work indicates that Phase I and II trials are already underway with SOS1 inhibitors, both as monotherapy and in combination with KRAS G12C inhibitors, in patients with advanced solid tumors that have alterations in the RAS-MAPK pathway. These combined strategies aim to extend the therapeutic benefit to patients with different RAS mutations and reduce the likelihood of the tumor escaping pharmacological blockade.
As highlighted by the authors of the review, the accumulated knowledge in recent years suggests that the future approach to RAS-driven tumors will need to target the pathway at different levels, integrating drugs directed against RAS with inhibitors or degraders of SOS1 and other pathway modulators.