The KRAS gene and its corresponding protein, K-Ras, are components of cellular communication and growth regulation. K-Ras acts as a molecular switch within the RAS/MAPK signaling pathway, relaying external signals to the cell’s nucleus. These signals direct cells to grow, divide, or develop specialized functions. K-Ras controls this switch by converting guanosine triphosphate (GTP) to guanosine diphosphate (GDP), effectively turning itself off.
Understanding KRAS and Its Role
The K-Ras protein functions as a GTPase, an enzyme that hydrolyzes GTP into GDP, thereby cycling between an active (GTP-bound) and inactive (GDP-bound) state. When K-Ras binds to GTP, it is “on” and transmits signals that promote cell proliferation and survival. This mechanism ensures controlled cell growth and division.
Mutations in the KRAS gene can disrupt this balance, causing the K-Ras protein to become permanently stuck in its “on” position. This continuous activation leads to uncontrolled cell proliferation and the formation of tumors. KRAS mutations are found in approximately 11.6% of all carcinomas and are prevalent in aggressive cancers. For instance, over 80% of pancreatic ductal adenocarcinomas (PDAC) harbor KRAS mutations, with G12D being the most common subtype. Colorectal cancer (CRC) has a KRAS mutation frequency of about 37.97%, and non-small cell lung cancer (NSCLC) shows mutations in approximately 21.20% of patients.
The Historical Challenge of Targeting KRAS
Historically, KRAS was considered an “undruggable” target in cancer therapy due to several challenges. The K-Ras protein possesses a smooth, spherical surface, making it difficult for small molecule drugs to find binding pockets. This hindered the development of high-affinity inhibitors.
K-Ras exhibits a high affinity for GTP, binding it in the picomolar range. This strong binding made competitive inhibition challenging, as it was difficult to design molecules that could effectively compete with GTP to turn the protein off. Despite decades of research and the recognition of KRAS mutations as cancer drivers, these biochemical properties prevented the successful development of direct KRAS inhibitors.
Recent Breakthroughs in KRAS-Targeted Therapies
The landscape of KRAS research shifted with the development of direct KRAS G12C inhibitors, transforming a previously “undruggable” target into a treatable one. Sotorasib (Lumakras) and adagrasib (Krazati) represent advancements in this area. These drugs specifically target the KRAS G12C mutation, characterized by a cysteine residue at codon 12. This unique cysteine residue creates a transiently accessible “switch II pocket” in the inactive, GDP-bound state of the KRAS G12C protein.
Sotorasib and adagrasib work by covalently and irreversibly binding to this specific cysteine residue within the switch II pocket. This binding locks the KRAS G12C protein in its inactive, GDP-bound state, preventing it from binding to GTP and shutting down the aberrant signaling pathways that drive tumor growth. By trapping the protein in this inactive conformation, these inhibitors effectively block the downstream phosphorylation cascades involving RAF, MEK, and ERK, responsible for uncontrolled cell proliferation.
Sotorasib received accelerated approval from the FDA in May 2021 for patients with KRAS G12C-mutated advanced NSCLC. Adagrasib also received accelerated approval in December 2022 for advanced KRAS G12C-mutated NSCLC and in June 2024, in combination with cetuximab, for KRAS G12C-mutated colorectal cancer. These approvals offer new therapeutic options for patients with these specific KRAS-driven cancers.
The Evolving Landscape of KRAS Research
The success of KRAS G12C inhibitors has propelled research into broader KRAS-targeted strategies. Efforts are underway to develop inhibitors for other common KRAS mutations beyond G12C, such as G12D and G12V, which are prevalent in pancreatic and colorectal cancers. Novel approaches, including tri-complex inhibitors, are being explored to target the active, GTP-bound state of various KRAS variants. These compounds bind to an intracellular protein, cyclophilin A, forming a complex that sterically inhibits RAS interaction with its downstream effectors.
Researchers are also investigating combination therapies to enhance efficacy and overcome drug resistance, which can limit monotherapy effectiveness. Combining KRAS inhibitors with other targeted agents, such as receptor tyrosine kinases (RTKs), SHP2, or MEK, is showing promise in preclinical and clinical trials. For instance, combining KRAS G12C inhibitors with EGFR inhibitors has demonstrated efficacy in KRAS G12C-mutated colorectal cancer. Immunotherapies and chemotherapies combined with KRAS inhibitors are also being explored to improve patient outcomes and durable tumor elimination.
Overcoming acquired resistance to KRAS inhibitors is another area of focus, as cancer cells can bypass initial drug effects. This involves understanding how cells reactivate MAPK signaling or develop new mutations that confer resistance. The development of pan-RAS inhibitors, which target multiple RAS isoforms, and inhibitors that specifically target the active (on) state of KRAS are also being investigated to address this challenge and broaden the applicability of KRAS-targeted therapies.