KRAS Inhibitors: Targeting the 'Undruggable' Mutation in 2025 and Beyond

Once deemed "undruggable" due to its smooth surface and high affinity for GTP, the KRAS oncogene has become a prime target in precision oncology. KRAS mutations drive approximately 20-30% of all cancers, with high prevalence in non-small cell lung cancer (NSCLC, ~30%), colorectal cancer (CRC, ~40%), and pancreatic ductal adenocarcinoma (PDAC, >90%). The most common mutation historically was G12C, but breakthroughs now extend to G12D, G12V, and multi-selective "pan-KRAS" approaches.

As of December 2025, significant progress has transformed treatment landscapes, particularly for previously intractable cancers like PDAC.

Key Breakthroughs in KRAS G12C Inhibitors

The pioneering covalent inhibitors sotorasib (Lumakras) and adagrasib (Krazati), approved earlier for KRAS G12C-mutated NSCLC, saw major expansions in 2025:

• January 2025 FDA approval: Sotorasib combined with panitumumab (Vectibix, an EGFR inhibitor) for previously treated KRAS G12C-mutated metastatic CRC. This combination addresses adaptive resistance via EGFR feedback, achieving higher objective response rates (ORR ~26%) and progression-free survival (PFS ~5.6 months) compared to monotherapy.

Next-generation G12C inhibitors like olomorasib and divarasib show promise in overcoming resistance, with ongoing trials exploring first-line combinations with immunotherapy.Advances Beyond G12C: Targeting G12D and Multi-Selective InhibitorsG12D dominates in PDAC (~50% of KRAS mutations) and is common in CRC, historically lacking targeted options. 2025 marked exciting progress:

• Daraxonrasib (RMC-6236): A RAS(ON) multi-selective inhibitor targeting active GTP-bound RAS (G12X, G13X, Q61X). In phase 1 trials for previously treated KRAS G12X-mutated metastatic PDAC, it achieved median PFS of 8.8 months and deep tumor regressions. The FDA granted Breakthrough Therapy Designation in mid-2025, highlighting its potential in this deadly cancer.
• VS-7375 (GFH375): An oral KRAS G12D (ON/OFF) selective inhibitor received Fast Track Designation for advanced PDAC (first- or second-line). Early phase 1/2 data showed promising safety and preliminary efficacy.

Other candidates like HRS-4642 and zoldonrasib (G12D-selective) are advancing, with preclinical models demonstrating tumor regression in PDAC and CRC.Pan-KRAS and Pan-RAS StrategiesTo address multiple mutations simultaneously:

• Inhibitors like JAB-23E73 and BBO-11818 entered early clinical trials in 2025, showing broad activity against G12D/V and others in preclinical models.
• Revolution Medicines' pipeline (including elironrasib for G12C) emphasizes tri-complex mechanisms for enhanced potency.

These approaches aim to overcome mutation heterogeneity and resistance.Challenges: Resistance MechanismsDespite advances, resistance limits durability:

• Acquired: Secondary KRAS mutations (e.g., Y96D), pathway reactivation (MAPK/PI3K), MET/EGFR amplification.
• Adaptive/Intrinsic: Bypass signaling, epithelial-to-mesenchymal transition, or aberrant KRAS localization (e.g., cytoplasmic in HER2-amplified tumors).
• Combinations (e.g., with EGFR, SHP2, or MEK inhibitors) and next-gen agents targeting RAS(ON) states are key strategies to delay resistance.

Future Outlook2025 has been a pivotal year, with the first approvals beyond NSCLC and breakthrough designations signaling hope for PDAC patients. Ongoing trials focus on combinations, earlier-line use, and pan-KRAS inhibitors to achieve deeper, longer-lasting responses. Biomarker testing for KRAS mutations is now essential, paving the way for personalized therapies against this once-elusive target.
These developments substantiate a shift: KRAS is no longer undruggable, offering new hope for millions affected by KRAS-driven cancers.