For decades, it was cancer's ultimate survivalist. Now, science is finally closing in on one of oncology's most elusive targets.
Imagine a microscopic switch stuck in the "on" position, relentlessly driving uncontrolled cancer growth within cells. This is the reality of mutant KRAS, a protein that has evaded targeted treatment for over four decades despite being one of the most common drivers of human cancer. Found in a quarter of all human tumors, KRAS mutations are particularly prevalent in some of the deadliest cancers—pancreatic, colorectal, and lung cancers 5 .
This article explores the remarkable scientific journey from considering KRAS "undruggable" to developing innovative therapies that are now extending patients' lives.
KRAS is a protein that normally acts as a careful molecular switch within cells, cycling between active (GTP-bound) and inactive (GDP-bound) states to regulate growth 5 7 . When mutated, however, this switch becomes stuck in the "on" position, leading to continuous signaling for cell proliferation and survival 8 .
The KRAS protein contains a G-domain with specific regions crucial to its function: the P-loop and two flexible regions known as Switch I and Switch II 5 9 . These areas are essential for binding to nucleotides (GDP/GTP) and interacting with other cellular proteins. Mutations primarily occur at codons 12, 13, or 61, with the G12C mutation (where glycine is replaced by cysteine at position 12) being particularly common in lung cancer 7 .
When locked in its active state, mutant KRAS continuously activates downstream signaling pathways.
Primarily drives cell proliferation
Promotes cell survival and metabolism
This constant signaling not only drives uncontrolled cancer growth but also reshapes the tumor microenvironment, creating conditions that suppress immune responses and facilitate cancer's spread 5 .
The breakthrough in targeting KRAS came from a clever strategy focused on the KRAS G12C mutation. Researchers discovered they could exploit the unique cysteine residue created by this mutation to design drugs that irreversibly bind to KRAS, locking it in an inactive state 7 9 .
The first two drugs to emerge from this approach—sotorasib (AMG510) and adagrasib (MRTX849)—paved the way for FDA approvals and established KRAS as a truly "druggable" target 7 .
Since these initial breakthroughs, the field has expanded rapidly with next-generation inhibitors showing improved efficacy. D3S-001, a newer KRAS G12C inhibitor, has demonstrated promising results in clinical trials, achieving tumor shrinkage in over 70% of treatment-naïve patients and showing activity even in patients who had developed resistance to earlier KRAS inhibitors 6 .
KRAS identified as human oncogene
First direct KRAS G12C inhibitors discovered
Sotorasib becomes first FDA-approved KRAS inhibitor
Adagrasib receives FDA approval
Next-generation inhibitors and combination therapies in development
While G12C inhibitors marked a crucial first victory, they address only one specific mutation. Scientists are now developing strategies to target other KRAS mutations, particularly the G12D variant which is more common in pancreatic and colorectal cancers 1 9 .
Recent ESMO Congress 2025 data revealed several promising candidates:
These developments represent important steps toward broader targeting of KRAS mutations beyond G12C.
| Drug Name | Target | Mechanism | Efficacy in Key Cancers |
|---|---|---|---|
| HRS-4642 | KRAS G12D | Non-covalent inhibitor | NSCLC: 23.7% ORR, PDAC: 20.8% ORR 1 |
| ASP3082 | KRAS G12D | Protein degrader | Preclinical data shows promising approach 1 |
| INCB161734 | KRAS G12D | Non-covalent inhibitor | PDAC: 20% ORR at 600 mg dose 1 |
| D3S-001 | KRAS G12C | Next-generation inhibitor | 70% ORR in treatment-naïve patients 6 |
G12C mutation prevalence: ~13%
Primary target for first-generation inhibitors
G12D mutation prevalence: ~36%
Focus for next-generation inhibitors
Despite these advances, resistance to KRAS inhibitors remains a significant challenge. Cancer cells often find ways to bypass targeted treatments, frequently through MYC protein upregulation, which promotes continued tumor growth despite KRAS inhibition 3 .
To address this limitation, researchers developed an innovative "inverted chimeric RNAi" molecule that simultaneously targets both KRAS and MYC 3 . This novel approach involved:
Identifying potent siRNA sequences against both KRAS and MYC through computational design and experimental validation 3
Creating a fused molecule combining the passenger strand of a MYC-targeting siRNA with the guide strand of a KRAS-targeting siRNA 3
Adding chemical modifications (2'-O-methyl and 2'-fluoro groups plus phosphorothioates) to enhance stability and reduce immune activation 3
Conjugating with targeting ligands (such as EGFR-targeting molecules) to improve tumor-specific delivery 3
The chimeric RNAi approach demonstrated remarkable effectiveness:
10- to 40-fold improvement in inhibiting cancer viability compared to individual siRNAs 3
Enhanced metabolic stability in tumors and improved silencing of both oncogenes 3
This innovative strategy establishes proof of concept for simultaneously targeting two "undruggable" proteins and could be broadly applied to other challenging cancer targets.
| Research Tool | Primary Function | Research Application |
|---|---|---|
| KRAS G12C inhibitors (AMG510, MRTX849) | Irreversibly bind mutant KRAS G12C | Establish baseline KRAS inhibition efficacy 7 9 |
| Chimeric siRNA molecules | Simultaneously target KRAS and MYC mRNA | Overcome resistance mechanisms 3 |
| Lentiviral vectors | Introduce genetic modifications | Create knockout cell lines (KEAP1, STK11) 2 |
| Circulating tumor DNA (ctDNA) analysis | Monitor tumor DNA in blood | Early response assessment 1 |
| Patient-derived xenografts | Grow human tumors in mice | Preclinical drug testing 3 |
The path forward for KRAS-targeted therapies lies in combination strategies and better patient selection. Researchers are increasingly focusing on:
The remarkable progress in targeting KRAS demonstrates how persistence, creativity, and scientific collaboration can transform cancer treatment. From an "undruggable" target to a growing arsenal of precision medicines, the journey to tame the KRAS cancer beast continues to accelerate, offering new hope for patients with some of the most challenging cancers.