RAS inhibitors represent a significant advancement in cancer treatment, offering new hope for patients. These therapies directly target proteins once considered impossible to modify with drugs. This innovative approach addresses a fundamental driver of many cancers, holding promise for improved patient outcomes.
The RAS Protein and Cancer Development
The RAS protein family (HRAS, KRAS, and NRAS) functions as molecular switches within cells, orchestrating growth, division, and survival. Normally, RAS proteins cycle between inactive (GDP-bound) and active (GTP-bound) forms, relaying signals from outside the cell to the nucleus. This precise regulation ensures controlled cellular processes.
However, mutations in RAS genes can permanently lock these proteins in their active state, leading to uncontrolled cell proliferation and tumor formation. These “oncogenic” mutations disrupt normal regulatory mechanisms, causing cells to divide relentlessly. Such mutations are highly prevalent, occurring in over 30% of all human cancers.
The KRAS isoform accounts for approximately 85% of all RAS mutations in human cancers. KRAS mutations are frequently found in some of the deadliest malignancies, including nearly all pancreatic cancers, about half of colorectal cancers, and roughly one-third of lung cancers. Specific mutations at codons 12, 13, or 61 are associated with tumor development, such as the G12D mutation in KRAS, a frequent change in colorectal cancer.
Targeting RAS Pathways with Inhibitors
Historically, directly targeting RAS proteins was considered a formidable challenge in drug development due to their smooth, spherical structure, which lacked obvious binding pockets. For decades, RAS was labeled “undruggable,” leading researchers to focus on inhibiting downstream effectors of the RAS pathway. This indirect approach often yielded limited success due to the complexity and redundancy of cellular signaling.
A major breakthrough came with the discovery of direct covalent inhibitors specifically targeting the KRAS G12C mutation. These inhibitors exploit a unique cysteine residue created by the G12C mutation, forming an irreversible bond that locks the protein in its inactive GDP-bound state. This prevents KRAS G12C from switching to its active, GTP-bound form, halting the aberrant signaling that drives cancer growth.
Other strategies are being explored to disrupt RAS signaling. These include blocking upstream regulators that activate RAS or inhibiting various downstream proteins in the RAS signaling cascade, such as the Raf-MEK-ERK pathway. Novel approaches are also emerging, like tri-complex inhibitors that target the active, GTP-bound state of RAS by forming a complex with an intracellular protein like cyclophilin A, sterically hindering RAS interaction with its effectors.
Approved RAS Inhibitors and Clinical Progress
The development of direct KRAS G12C inhibitors marked a significant turning point in cancer therapy. Sotorasib was the first direct KRAS G12C inhibitor to receive accelerated FDA approval in May 2021. It is approved for advanced non-small cell lung cancer (NSCLC) with the KRAS G12C mutation that progressed after at least one prior systemic treatment. This approval was based on results from the CodeBreak 100 trial, a phase II study demonstrating an objective response rate for sotorasib monotherapy.
Following sotorasib, adagrasib received accelerated FDA approval in December 2022 for the same indication. The KRYSTAL-1 trial, a phase I/II study, supported adagrasib’s approval by showing an objective response rate of 42.9% and a median progression-free survival of 6.5 months. Both sotorasib and adagrasib are recommended subsequent therapies for KRAS G12C-mutated NSCLC.
While effective in NSCLC, their application is being investigated in other cancer types with KRAS G12C mutations. The CodeBreak 100 trial, for example, included patients with advanced KRAS G12C-mutated colorectal cancer and pancreatic ductal adenocarcinoma, showing initial anti-tumor activity. Ongoing clinical trials continue to evaluate the safety and efficacy of these inhibitors in metastatic NSCLC, aiming to refine treatment strategies.
Future Directions in RAS Inhibition
Despite the success of KRAS G12C inhibitors, overcoming drug resistance remains a challenge in RAS-mutated cancers. Cancer cells can develop mechanisms to bypass these therapies, including activating mutations in other signaling pathways (e.g., EGFR or HER2), inactivating mutations in tumor suppressor genes, or gene amplifications (e.g., MET). This necessitates continued research into novel strategies.
Future efforts focus on developing inhibitors for other RAS mutations beyond G12C, such as KRAS G12D and G13C, prevalent in pancreatic and colorectal cancers. Researchers are exploring pan-RAS inhibitors, which target multiple RAS isoforms or mutations simultaneously, and compounds that inhibit the active, GTP-bound state of RAS regardless of the specific mutation. RMC-6236, for example, is a multi-selective inhibitor targeting active forms of KRAS, NRAS, and HRAS.
Combination therapies are also promising, with studies exploring synergistic effects of RAS inhibitors with other anti-cancer drugs, including immunotherapy. For instance, combining RAS inhibitors with agents that reactivate tumor suppressor proteins like DLC1 has shown potent activity in preclinical models. Novel therapeutic modalities, such as Proteolysis-Targeting Chimeras (PROTACs), are being investigated to degrade RAS proteins entirely, to overcome resistance and enhance therapeutic efficacy.