The Essential Role and Research Progress of RAS Proteins in Cell Biology and Cancer Therapy

RAS (Rat Sarcoma viral oncogene homolog) proteins are a superfamily of small membrane-bound GTPases that serve as core signaling switches in eukaryotic cells. Highly conserved throughout biological evolution, the mammalian RAS family consists of three canonical subtypes: KRAS, HRAS, and NRAS. These proteins anchor on the inner surface of the cell membrane and mediate signal transduction between extracellular microenvironmental stimuli and intracellular biological responses, participating in the regulation of almost all fundamental cellular processes. For over half a century, RAS has remained a hotspot in biomedical research, owing to its vital physiological functions and its status as one of the most potent oncogenic drivers in human malignant tumors.

Under normal physiological conditions, RAS proteins exert their regulatory functions through a dynamic and reversible GTP-GDP binding cycle. In the resting state, RAS binds to guanosine diphosphate (GDP) and maintains an inactive conformation. When cells receive extracellular growth factors, cytokines, or hormonal stimuli, upstream signaling molecules promote the dissociation of GDP and the binding of guanosine triphosphate (GTP), activating RAS proteins. Activated RAS further triggers and amplifies multiple downstream signaling cascades, among which the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR pathways are the most critical. These signaling axes collaboratively govern cell proliferation, differentiation, metabolic reprogramming, migration, and apoptosis, maintaining cellular homeostasis and ensuring the normal growth and renewal of tissues and organs.

Somatic mutations of RAS genes are closely correlated with the initiation, progression, and metastasis of human cancers, making RAS the most frequently mutated oncogene family in clinical malignancies. Statistically, RAS mutations account for nearly 30% of all human tumor cases, with distinct subtype-specific cancer preferences. KRAS mutations are the most prevalent, dominating in highly aggressive malignancies such as pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. NRAS mutations are commonly detected in melanoma and hematological tumors, while HRAS mutations are mainly associated with bladder and head and neck cancers. Most oncogenic RAS mutations occur at key functional sites such as G12, G13, and Q61, which severely impair the intrinsic GTPase activity of RAS proteins. This structural defect prevents mutant RAS from hydrolyzing bound GTP to GDP, locking it in a constitutively active state.

Persistent abnormal activation of mutant RAS leads to uncontrolled overactivation of downstream signaling pathways. The continuous stimulation of the MAPK pathway drives excessive cell proliferation and disrupts normal cell cycle checkpoints, while the hyperactive PI3K-AKT-mTOR pathway inhibits tumor cell apoptosis, reprograms cellular energy metabolism to support rapid tumor growth, and enhances the invasive and metastatic capabilities of malignant cells. Additionally, aberrant RAS signaling also mediates tumor immune microenvironment suppression and chemotherapy resistance, further worsening patient prognosis. For decades, mutant RAS was classified as an “undruggable” therapeutic target due to its compact molecular structure, lack of specific small-molecule binding pockets, and high affinity for endogenous GTP.

In recent years, breakthroughs in structural biology and targeted drug development have overturned this long-standing cognition. The successful development of covalent KRAS G12C inhibitors has achieved landmark progress in RAS-targeted therapy. These novel drugs can specifically bind to the mutant cysteine residue generated by KRAS G12C mutation, block the persistent activation of RAS signaling, and effectively inhibit the proliferation of RAS-mutant tumor cells. Currently, multiple KRAS G12C inhibitors have been approved for clinical treatment, bringing precise therapeutic options for patients with advanced RAS-mutant solid tumors and significantly improving their long-term survival rates. Moreover, emerging research has found that RAS dysregulation is not limited to tumors but also participates in the pathogenesis of inflammatory diseases, metabolic disorders, and developmental malformations, expanding the research boundary of RAS biological functions.

In conclusion, RAS proteins are irreplaceable core regulators of cellular signaling networks. Their normal function sustains cellular life activities, while their abnormal activation triggers multiple disease processes. In-depth exploration of RAS protein structural characteristics, signaling regulatory mechanisms, and drug resistance mechanisms will not only deepen human understanding of cell biology and tumor pathogenesis but also promote the development of broader and more precise targeted therapeutic strategies, laying a solid foundation for the clinical treatment of RAS-related diseases.