The Ras protein family, including KRAS, HRAS, and NRAS, plays a central role in relaying signals that govern cell growth and survival. These proteins are classified as small GTPases, functioning as molecular switches within the cell’s signaling network. Ras proteins translate external messages, such as those from growth factors, into internal instructions that tell the cell when to divide, mature, or survive. This family is one of the most frequently mutated in human cancers, with genetic alterations found in about 20% to 30% of all tumors. When Ras malfunctions, it becomes a primary driver of uncontrolled cellular growth and is directly implicated in the development of malignancies.
Normal Role as a Molecular Switch
The function of the Ras protein is based on a precise on/off mechanism dictated by two molecules: Guanosine Triphosphate (GTP) and Guanosine Diphosphate (GDP). Ras is considered “on” when it is bound to the high-energy molecule GTP, which causes a conformational change that allows it to interact with other proteins. Conversely, Ras is “off” when it is bound to the lower-energy molecule GDP, which locks it in an inactive shape.
Guanine nucleotide Exchange Factors (GEFs) turn the switch on by promoting the release of GDP from Ras and facilitating the binding of GTP. Once Ras is bound to GTP, it possesses a slow, intrinsic ability to convert GTP back to GDP, a process called GTP hydrolysis. GTPase-Activating Proteins (GAPs) accelerate this hydrolysis reaction, quickly returning Ras to its inactive, GDP-bound state. This managed cycle ensures that cellular growth signals are transient and regulated.
Downstream Effects on Cell Function
When the Ras switch is turned on, it transmits signals deeper into the cell by interacting with downstream effector proteins. Two major signaling cascades activated by Ras are the Mitogen-Activated Protein Kinase (MAPK) pathway and the Phosphoinositide 3-Kinase (PI3K) pathway. The MAPK pathway, involving a sequential chain of protein kinases (Raf, MEK, and ERK), is primarily responsible for transmitting signals that lead to cell proliferation and differentiation. Activation of this cascade promotes cell division and growth.
The PI3K pathway is the other major branch of Ras signaling, centrally involved in cell survival, metabolism, and motility. When activated by Ras, PI3K initiates a cascade that includes the protein Akt, which then phosphorylates numerous targets to inhibit apoptosis, or programmed cell death. The combined activation of both the MAPK and PI3K pathways ensures that a cell receives instructions for growth and division, along with the necessary survival signals. This normal, coordinated signaling is crucial for tissue maintenance and development.
How Ras Becomes an Oncogene
The transformation of a normal Ras protein into a cancer-driving oncogene occurs through genetic errors in the RAS genes. These mutations are found in about 30% of all human cancers, with the KRAS isoform being the most frequently mutated, accounting for about 75% of all Ras-mutant cancers. The prevalence of KRAS mutations is especially high in pancreatic cancer (up to 90%), colorectal cancer (around 45%), and non-small cell lung cancer (NSCLC). Most pathological mutations occur at amino acid positions such as glycine at codon 12 (G12), glycine at codon 13 (G13), or glutamine at codon 61 (Q61).
Mutations like G12D, G12V, or G12C prevent the Ras protein from performing its GTP hydrolysis function. This structural change makes the mutated Ras protein insensitive to the regulatory “off” signal provided by GAPs. As a result, the oncogenic Ras protein is permanently locked in its active, GTP-bound state, leading to continuous and uncontrolled downstream signaling. This state of permanent activation, known as constitutive activation, constantly floods the cell with growth and survival signals, driving tumor formation.
Current Approaches for Targeting Ras
For nearly four decades, Ras was considered “undruggable” because its smooth surface lacked the pocket required for a small-molecule drug to bind and inhibit its function. The breakthrough came with the development of targeted therapies that exploit the unique structure of the KRAS G12C mutation. This specific mutation creates a cysteine residue at the 12th position, which offers a vulnerable site for drug binding.
New medications, such as sotorasib and adagrasib, are covalent inhibitors that target this cysteine residue. These drugs permanently bind to the KRAS G12C mutant protein, trapping it in its inactive, GDP-bound conformation and effectively blocking growth signals. While these drugs target the G12C subtype, which is most common in NSCLC, patients often develop resistance. Research is focused on developing pan-Ras inhibitors that can target the more prevalent G12D and G12V mutations seen in pancreatic and colorectal cancers. Other emerging strategies include combining KRAS inhibitors with drugs that block downstream pathways like MAPK, or using agents to prevent Ras from localizing to the cell membrane where it must reside to be active.