Ras proteins are a family of proteins that act as molecular switches within cells. They transmit signals from outside the cell to the nucleus, playing a role in various cellular processes. These proteins are widely present across all animal cell lineages and organs. Their proper functioning is significant for human health, and their malfunction can contribute to various diseases, including cancer.
How Ras Proteins Work Normally
Ras proteins function as molecular switches, cycling between an active “on” state and an inactive “off” state. In their inactive state, Ras proteins are bound to guanosine diphosphate (GDP). When activated by incoming signals, guanine nucleotide exchange factors (GEFs) exchange GDP for guanosine triphosphate (GTP), switching Ras to its active “on” state.
The active Ras-GTP complex then binds to “effector” molecules, initiating downstream signaling pathways that relay messages within the cell. These pathways regulate cellular processes such as cell growth, division, and differentiation. To return to the inactive state, Ras possesses an intrinsic GTPase activity that hydrolyzes GTP back to GDP. This process is accelerated by GTPase-activating proteins (GAPs), which promote GTP hydrolysis.
When Ras Proteins Go Rogue
When mutations occur in the genes encoding Ras proteins, they can become locked in an “on” state. These mutations impair the protein’s ability to hydrolyze GTP to GDP, leading to persistent activation. The unregulated activity of these mutant Ras proteins drives uncontrolled cell growth and division, a characteristic of cancer development.
These mutations are considered “oncogenic,” meaning cancer-causing, due to their ability to promote aberrant signaling for cell proliferation. Ras mutations are prevalent in human cancers, found in 20% to 25% of all human tumors. In certain cancer types, the frequency is higher; for instance, Ras mutations are found in most pancreatic cancers (90%), about half of colorectal cancers (40-50%), and up to 30% of lung cancers. The KRAS isoform accounts for about 85% of all Ras mutations in cancer.
Targeting Ras in Disease
Historically, developing drugs that directly target Ras proteins has been challenging, leading to their reputation as “undruggable.” This difficulty stems from the absence of deep binding pockets suitable for small molecule inhibitors within the protein structure. Despite these challenges, breakthroughs have emerged in recent years, with the development of direct inhibitors for specific mutated forms of Ras, such as KRAS G12C.
Current therapeutic strategies involve several approaches. Direct inhibitors, like sotorasib, selectively target specific mutant Ras proteins, preventing them from remaining in their active state. Other approaches focus on targeting downstream effectors, the proteins Ras activates in signaling pathways, such as the Raf/MEK/ERK and PI3K pathways. Researchers are also exploring synthetic lethality, a strategy that involves targeting a protein a cancer cell with a Ras mutation depends on for survival, while normal cells do not. These ongoing research efforts aim to develop more effective treatments for Ras-driven cancers.