The Notorious KRAS

For decades, the KRAS gene has been the quintessential "undruggable" target in oncology. This notorious gene is a key driver in some of the most aggressive and lethal cancers, including pancreatic, colorectal, and non-small cell lung cancer and has long defied therapeutic intervention. Researchers viewed KRAS as a difficult target due to its challenging biochemical properties including a smooth topography devoid of conventional binding sites and a picomolar affinity for its GTP/GDP signaling partners. The breakthrough came not from overcoming these hurdles head-on, but by exploiting a specific vulnerability. This innovative strategy has successfully translated from the laboratory to the clinic, fundamentally changing the treatment landscape and proving that even the most difficult-to-drug proteins can become viable therapeutic targets with persistent scientific effort.

Physiological Function and Role in Signal Transduction

KRAS (Kirsten rat sarcoma viral oncogene homolog) is one of three human RAS genes, alongside HRAS and NRAS. These genes encode small GTPase proteins that act as molecular switches within cells.In its normal physiological role, the KRAS protein cycles between an active (GTP-bound) and an inactive (GDP-bound) state. This cycle is tightly regulated by other proteins:

• GEFs (Guanine Nucleotide Exchange Factors): These proteins help KRAS release GDP and bind to GTP, thereby activating it.

• GAPs (GTPase-Activating Proteins): These proteins enhance the intrinsic GTPase activity of KRAS, helping it hydrolyze GTP back to GDP, thus inactivating it.

When KRAS is in its active, GTP-bound state, it initiates a cascade of downstream signaling pathways. The most well-known and critical pathway is the MAPK (Mitogen-Activated Protein Kinase) pathway (RAS-RAF-MEK-ERK). This pathway ultimately leads to changes in gene expression that promote cell proliferation, differentiation, and survival. Other important downstream pathways include the PI3K-AKT-mTOR pathway, which regulates cell growth and metabolism. This intricate signaling network ensures that cells grow and divide only when necessary, responding appropriately to external cues.

The RAS–RAF–MEK–ERK pathway highlighting signal transduction from phosphorylation of growth factor receptors to expression of cell survival proteins, one of the MAPK cascades facilitated through RAS proteins. (Oscler et al. 2022)

Mutations in KRAS Leading to Cancers

Mutations in the KRAS gene are among the most common oncogenic alterations in human cancers. These mutations typically lock the KRAS protein in its active, GTP-bound state, leading to constitutive activation of downstream signaling pathways, even in the absence of growth-promoting signals. This uncontrolled signaling drives unchecked cell proliferation and survival, characteristic of cancer. Specific KRAS mutations are found in a significant percentage of several aggressive cancers: approximately 30-45% of colorectal cancer cases and around 15-30% of non-small cell lung cancers (NSCLC), particularly adenocarcinomas. They also occur in a striking 80% or more of pancreatic ductal adenocarcinomas (PDAC), making it a hallmark of this highly lethal cancer. 

The most frequent mutations occur at specific "hotspot" codons, primarily G12 (glycine at position 12), G13, and Q61. The KRAS G12C mutation is particularly prevalent in lung cancer and has recently become a major focus of therapeutic development.

An "Undruggable Target"

For decades, KRAS was famously labeled an "undruggable" target. This designation stemmed from several fundamental challenges:

1. Lack of a Suitable Binding Pocket: The KRAS protein has a very smooth surface with no obvious deep, hydrophobic pockets where a small molecule drug could bind effectively and specifically to inhibit its activity.

2. High Affinity for GTP: KRAS binds to GTP with extremely high affinity (in the picomolar range), making it incredibly difficult for a competitive inhibitor to displace natural GTP.

3. Constitutive Activity: The activating mutations essentially "lock" KRAS in its active state, making it less responsive to inhibitors that might target the transition between active and inactive forms.

4. Ubiquitous Nature: RAS proteins are critical for normal cellular function, raising concerns that any inhibitor might cause widespread, unacceptable side effects by interfering with healthy cells.

These factors made it incredibly challenging to develop drugs that could directly bind to and inhibit mutated KRAS without also disrupting the vital functions of normal KRAS or other related proteins.

Current Therapeutic Research and Clinical Progress

Despite the historical challenges, the landscape for KRAS-targeted therapies has dramatically shifted in recent years, moving KRAS from "undruggable" to "druggable." This breakthrough is largely due to the discovery of covalent inhibitors that specifically target the KRAS G12C mutation.

1. Direct KRAS G12C Inhibitors

The major breakthrough came with the development of drugs that exploit a unique characteristic of the KRAS G12C mutation: the presence of a cysteine residue at position 12. This cysteine contains a reactive sulfhydryl group that can form a covalent bond with specific small molecules.

• Sotorasib (Lumakras): Approved in 2021 by the FDA and in 2022 by the PMDA (Japan's regulatory agency), Sotorasib was the first-in-class KRAS G12C inhibitor. It selectively and irreversibly binds to the mutant cysteine, locking KRAS G12C in its inactive GDP-bound state. It has shown significant efficacy in patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) after at least one prior systemic therapy.

• Adagrasib (Krazati): Also a selective and irreversible KRAS G12C inhibitor, Adagrasib was approved by the FDA in 2022 for NSCLC and is currently undergoing review in Japan. It has shown promising results in NSCLC and is being investigated in other KRAS G12C-mutated cancers, including colorectal cancer and pancreatic cancer.

Several other G12C inhibitors are in various stages of clinical development, reflecting the intense interest in this area (See Table).

2. Pan-RAS and Other KRAS Mutant Strategies

While G12C inhibitors are a major success, they only address one specific mutation. Research continues into strategies that could target other common KRAS mutations (like G12D, G12V, G13D) or even pan-RAS activity:

• SOS1 Inhibitors: SOS1 is a GEF that activates RAS proteins. Inhibiting SOS1 could prevent RAS activation, particularly in cancers driven by non-G12C KRAS mutations where the protein still requires upstream activation.

• Synthetic Lethality Approaches: This involves identifying genes that, when inhibited, are selectively lethal to cancer cells with a KRAS mutation but spare normal cells such as targeting proteins involved in the MAPK or PI3K pathways downstream of KRAS.

• Immunotherapy Combinations: Combining KRAS inhibitors with immunotherapies (like checkpoint inhibitors) is an active area of research, hoping to leverage the synergistic effects of direct tumor cell targeting and immune system activation.

• Transcriptional Regulation: Approaches that aim to reduce the overall expression of the KRAS protein.

Table: Clinical Progress of KRAS-targeting drug development

The recent clinical successes with selective KRAS G12C inhibitors have not only validated this persistence but have also reignited a sense of optimism throughout the field. This initial success has paved the way for a new generation of therapeutic strategies. Researchers are now exploring ways to target other common KRAS mutations, such as G12D and G12V, which are prevalent in pancreatic and colorectal cancers. This ongoing research promises to further erode the "notorious" reputation of KRAS, offering a future where this once-invincible oncogene is no longer a death sentence but a manageable, treatable condition.

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Product validation

Immobilized HLA-A*11:01&B2M&KRAS G12D (VVVGADGVGK) TCR at 5ug/ml (100ul/well) on the plate. Dose response curve for Human HLA-A*11:01&B2M&KRAS G12D (VVVGADGVGK) Monomer, His Tag with the EC50 of 59.4ng/ml determined by ELISA (QC Test).

Immobilized HLA-A*11:01&B2M&KRAS G12D TCR at 2ug/ml (100ul/well) on the plate. Dose response curve for Biotinylated HLA-A*11:01&B2M&KRAS G12D (VVVGADGVGK) Monomer, His Tag with the EC50 of 0.1ug/ml determined by ELISA.

Immobilized Human HLA-A*03:01&B2M&KRAS G12V (VVVGAVGVGK) Tetramer, His Tag at 5ug/ml (100ul/Well) on the plate. Dose response curve for Anti-HLA-A*03:01&B2M&KRAS G12V (VVVGAVGVGK) Antibody, hFc Tag with the EC50 of 0.18ug/ml determined by ELISA (QC Test).

1E6 of KRAS G12V specific TCR-HEK293T cell line were stained with 100ul of 10ug/ml PE-Labeled Human HLA-A*11:01&B2M&KRAS G12V (VVVGAVGVGK) Tetramer Protein (Cat. No. MHC-HE005TP) and non-transfected HEK293T cells and PE-Labeled protein were used as negative controls. PE signal was used to evaluate the binding activity.

References:

Oscier, D., Stamatopoulos, K., Mirandari, A., & Strefford, J. (2022). The Genomics of Hairy Cell Leukaemia and Splenic Diffuse Red Pulp Lymphoma. Cancers, 14(3), 697. https://doi.org/10.3390/cancers14030697

Simanshu, D. K., et al. (2017). "RAS Proteins and Their Regulators in Human Disease." Cell, 170(1), 171-182. This review provides an in-depth look at the physiological function of RAS proteins and their role as molecular switches.

Hobbs, G. A., et al. (2016). "KRAS: From Undruggable to a Druggable Oncogene." Cancer Cell, 30(2), 177-187. This article discusses the historical challenges of targeting KRAS and the emerging strategies.

Canon, J., et al. (2019). "The Clinical Efficacy of Sotorasib, a KRAS G12C Inhibitor, in Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer." New England Journal of Medicine, 381(7), 633-643. This is a key clinical trial for sotorasib, providing data on its efficacy.

Janjigian, Y. Y., et al. (2020). "Adagrasib (MRTX849) as a Targeted Therapy for KRAS G12C-Mutated Advanced Solid Tumors." New England Journal of Medicine, 383(13), 1261-1270. This pivotal trial establishes the clinical utility of adagrasib.

Spandidos, D. A. (2025). "Targeting KRAS in colorectal cancer (Review)." Molecular and Clinical Oncology. This review focuses on KRAS mutations in colorectal cancer and the emerging therapeutic strategies.

Lito, P., et al. (2016). "PD-1 Blockade and KRAS Inhibition in a Mouse Model of Pancreatic Cancer." Nature, 539(7627), 415-419. This study illustrates the historical difficulty in targeting KRAS and highlights a significant preclinical breakthrough.

Ostrem, J. M., et al. (2013). "K-Ras(G12C) Inhibitors Allosterically Control the G-S-I Conformation to Inhibit Signaling." Nature, 496(7446), 496-500. A seminal paper that describes the discovery of the first small-molecule inhibitors of KRAS G12C, which led to the development of sotorasib and adagrasib.

Blakely, C. M., et al. (2022). "Combinatorial Strategies to Overcome Resistance to KRAS G12C Inhibitors." Journal of Clinical Oncology, 40(10), 1145-1153. This review article discusses the combination therapies being developed to improve outcomes with KRAS inhibitors.

Wang, Y., et al. (2025). "Advancements in gene therapies targeting mutant KRAS in cancers." Pharmacology & Therapeutics. This review explores the broader landscape of KRAS research beyond G12C inhibitors, including pan-RAS and gene therapies.