Targeted therapy is a major advance in oncology, designed to block specific molecular changes that drive cancer growth while sparing healthy cells. This precision approach relies on identifying genetic alterations that serve as the tumor’s Achilles’ heel. The KRAS gene is a dominant oncogene implicated in millions of cancer cases worldwide. Mutations in KRAS are particularly prevalent in aggressive malignancies, including cancers of the lung, pancreas, and colon. For decades, the KRAS protein posed a profound challenge to drug developers, but recent scientific breakthroughs have finally begun to turn this once-intractable target into a treatable one.
The Role of the KRAS Oncogene in Cancer Development
The KRAS gene encodes a small protein belonging to the Ras superfamily, functioning as a molecular switch that regulates fundamental cellular processes like growth, division, and survival. The protein cycles between two conformations: an inactive “off” state (bound to guanosine diphosphate, GDP) and an active “on” state (bound to guanosine triphosphate, GTP). Guanine nucleotide exchange factors facilitate the switch to the active form by promoting GDP release so GTP can bind.
Once KRAS is active and GTP-bound, it engages downstream signaling cascades, notably the RAF-MEK-ERK pathway, which relays the growth signal to the cell nucleus. The switch is normally turned off by the protein’s intrinsic GTPase activity, which hydrolyzes GTP back to GDP. However, oncogenic mutations, most frequently occurring at codon 12, disrupt this regulatory mechanism.
These mutations, often involving the substitution of Glycine (G) for another residue, prevent the mutated protein from effectively hydrolyzing GTP. This failure locks the KRAS protein permanently in its active, GTP-bound conformation, leading to continuous activation of pro-growth signaling pathways. This persistent cellular proliferation drives tumor development. Oncogenic KRAS mutations are found in approximately 90% of Pancreatic Ductal Adenocarcinoma, 40% of Colorectal Cancer, and 25% of Non-Small Cell Lung Cancer cases.
Overcoming the Historical “Undruggable” Status
For many years, KRAS was deemed “undruggable” by the pharmaceutical industry due to its unique biophysical properties. The primary obstacle was the protein’s smooth, globular structure, which lacked the deep, well-defined pockets required for small-molecule drugs to bind effectively. Most successful drugs fit into these depressions, but KRAS offered no easy entry point.
A secondary challenge was the protein’s high affinity for its native substrate, GTP, which is in the picomolar range. Developing a competitive inhibitor capable of displacing GTP from the active site was considered nearly impossible. The synthetic drug would need to bind with an even greater strength, making traditional drug design strategies ineffective for KRAS.
The eventual breakthrough required a fundamental shift in approach, moving away from targeting the active site directly. Researchers began searching for allosteric sites—secondary pockets that, when bound by a drug, alter the protein’s function indirectly. This search identified a transient, previously unknown pocket near the switch II region of the protein. The discovery of this hidden vulnerability was the first step in designing molecules that could engage the KRAS protein.
Current Approved KRAS G12C Inhibitors
The discovery of the hidden switch II pocket coincided with the understanding of a specific KRAS variant: the G12C mutation, where Glycine is replaced by Cysteine at position 12. This alteration proved key to unlocking a therapeutic strategy. The Cysteine residue, unlike the original Glycine, possesses a reactive chemical group known as a thiol side chain.
This unique chemical feature created an opportunity for a drug to bind irreversibly through covalent inhibition. G12C inhibitors were engineered to form a permanent chemical bond with this Cysteine residue. These inhibitors preferentially bind KRAS G12C when it is in its inactive, GDP-bound state, effectively trapping the protein in the “off” conformation and preventing it from switching to the GTP-bound state.
This mechanism led to the development and approval of the first-in-class drugs, Sotorasib and Adagrasib. Sotorasib was the first to receive accelerated approval, demonstrating clinical activity primarily in Non-Small Cell Lung Cancer (NSCLC) patients harboring the G12C mutation, which is the most common KRAS variant in NSCLC. Adagrasib followed with a similar mechanism, providing a second option. These agents have shown objective response rates in NSCLC previously unseen with conventional therapies, transforming the treatment landscape for this patient subset. Their application is also being explored in other G12C-mutated solid tumors, including Colorectal Cancer.
Expanding the Scope: Targeting Non-G12C KRAS Mutations
Despite the success of G12C inhibitors, the majority of KRAS-mutated cancers are driven by other variants, such as G12D, G12V, and G13D. The G12D mutation is the most common subtype in Pancreatic Ductal Adenocarcinoma, a cancer with a poor prognosis. Since these non-G12C variants lack the reactive Cysteine residue, they are not susceptible to current covalent inhibitors, necessitating new therapeutic strategies.
One active area of research involves developing direct inhibitors for the G12D variant, which uses an Aspartic acid residue instead of Cysteine. These next-generation compounds are designed as non-covalent inhibitors, binding reversibly to the protein. They often target the same Switch II pocket but do not rely on a chemical reaction with a Cysteine residue. Early clinical data for G12D-selective molecules have shown promise, indicating that non-G12C variants may also be directly targetable.
Other approaches focus on exploiting the vulnerabilities of KRAS-mutant cells through synthetic lethality. This involves combining a drug that targets a non-KRAS protein with an inhibitor that targets a downstream pathway, causing cell death only in the mutant cells. Researchers are exploring agents that target the DNA Damage Repair pathway, which KRAS-mutant cells often rely on to survive. Additionally, combination strategies involving G12C inhibitors with agents that block downstream signaling, such as MEK or SHP2 inhibitors, are being tested to prevent bypass pathways that lead to drug resistance.