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KRAS Screening & Functional Profiling Services

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Overview

KRAS is the most frequently mutated oncogene in human cancers, present in approximately 30% of all tumors, with over 95% of RAS mutations occurring in KRAS. Mutations such as G12C, G12D, and G12V do not behave uniformly; they drive distinct signaling dynamics, pathway dependencies, and therapeutic responses. In the clinic, KRAS mutation status already guides treatment decisions. In drug development, it defines both opportunity and limitation, particularly in the context of inhibitor resistance and combination strategies.

Creative Biogene treats KRAS as a dynamic signaling node within oncogenic networks, moving beyond single-mutation testing. Our integrated workflow connects mutation profiling, functional validation, pathway activation analysis, and drug screening into a unified system—enabling KRAS to be evaluated as both a biomarker and a fully actionable drug target.

Figure 1. KRAS membrane localization and GDP/GTP switching, regulated by GEFs and GAPs, mediate signal transduction from receptors to intracellular pathways. (Huang L, et al., 2021)

Creative Biogene's Capabilities

Protein Purification

We provide a comprehensive panel of recombinant KRAS proteins, covering major mutant variants (G12C, G12D, G12V, G12R, G12S, G13D, G13C, Q61H) as well as HRAS and NRAS. Each protein batch is rigorously validated for purity and activity. Both GDP-loaded and nucleotide-free states are available to support diverse experimental requirements.

Protein-Protein Interaction Assays

We quantitatively assess compound interference with KRAS–SOS1 and KRAS–cRAF binding, yielding direct readouts of inhibition at the protein–protein interaction level.

SPR Binding Assays

Surface plasmon resonance (SPR) is employed to determine binding affinity and kinetics between compounds and KRAS variants. Both GDP- and GTP-bound states are covered, enabling detailed profiling of inhibitor engagement across different conformational states.

Cell–Based Proliferation Assays

Using a panel of Ba/F3 cells stably transfected with various KRAS mutants, we perform cell viability assays to confirm on–target activity and distinguish compound efficacy from non–specific cytotoxicity. Additional 2D and 3D cell models are available for deeper phenotypic assessment.

Gene & Pathway Coverage

While KRAS is the central focus, meaningful drug development requires a broader context. Our platform supports integrated analysis of:

CategoryGenes / Targets
KRAS Mutation SpectrumG12C, G12D, G12V, G13D, Q61H/L/R, A146T and rare non-canonical variants
Core RAS Pathway ComponentsNRAS, HRAS, BRAF, RAF1, MAP2K1/2 (MEK1/2), ERK1/2
Upstream RegulatorsEGFR, HER2, MET
Parallel & Compensatory PathwaysPIK3CA, PTEN, AKT1/2, mTOR
Synthetic Lethality & Resistance TargetsSTK11 (LKB1), KEAP1, CDK4/6, SHP2 (PTPN11), SOS1

Drug Screening Strategies

Screening is tailored to mutation-specific biology and pathway dependencies.

  • For KRAS G12C programs – Focus on covalent inhibitor activity, target engagement, and adaptive resistance mechanisms.
  • For non–G12C mutations (G12D, G12V, etc.) – Direct inhibitors are still emerging; we emphasize pathway modulation (MEK, SHP2, SOS1) and synthetic lethality approaches.

Combination screening is an integral part of our platform. We systematically evaluate KRAS inhibitors together with MEK, SHP2, or CDK4/6 inhibitors to identify synergistic effects and resistance-reversing combinations. High-throughput systems generate dose-response matrices and synergy scores.

In parallel, CRISPR–based functional screens can identify novel genetic dependencies in KRAS–mutant backgrounds, uncovering previously unrecognized therapeutic opportunities.

Model Systems

To bridge screening and biology, experiments are performed across multiple model systems:

  • 2D cell lines – for high-throughput initial screening
  • 3D organoid models – better recapitulate tumor architecture and drug penetration
  • Patient-derived xenograft (PDX) models and in vivo studies – for advanced validation in physiologically relevant settings

This multi-layer strategy ensures seamless progression from discovery to preclinical validation.

Data Integration & Translational Output

All data are integrated into a coherent report that connects mutation, function, and therapeutic implication. Deliverables include:

  • Mutation profiles with allele frequency quantification
  • Co-occurrence analysis with other oncogenic alterations
  • Pathway activation signatures
  • Drug response data for single agents and combinations

Findings are interpreted in the context of clinical evidence, supporting response prediction, resistance mechanism identification, and strategic decision-making in drug development.

Laboratory & Quality System

All services are performed in our BSL–2 laboratory under a quality management system aligned with international standards. Our infrastructure integrates:

  • High-throughput liquid handling
  • Advanced molecular interaction platforms
  • High–content imaging for phenotypic screening
  • Precision gene editing

Each project includes defined quality checkpoints and internal controls. Deliverables include raw data, validated protocols, statistical analysis, and a final integrated report suitable for both scientific review and regulatory preparation.

Start Your KRAS-Driven Discovery Program

Whether you are developing next-generation KRAS inhibitors, exploring synthetic lethality, or investigating resistance mechanisms, our platform provides a structured yet flexible framework to move forward with confidence. We work closely with each client to align experimental depth, turnaround time, and resource allocation—ensuring that every dataset directly supports your next decision.

FAQ

What types of samples or models can I start with?

You can start with purified protein, cell lines (engineered or patient-derived), tumor tissue, or even liquid biopsy samples. If you only have a target mutation in mind, we can also help generate custom CRISPR-edited cell models to match your specific KRAS variant.

Do I need to provide my own compound library?

Not necessarily. We can screen your proprietary compounds, or we can use our curated libraries of focused KRAS inhibitors, pathway modulators, and clinically relevant reference molecules. For combination screening, we help design the matrix and provide the necessary partner inhibitors.

Can you distinguish between direct KRAS binding and downstream pathway modulation?

Yes. Our tiered approach includes direct binding assays (SPR, HTRF), nucleotide exchange assays, and downstream phosphorylation readouts. This allows you to know whether a compound hits KRAS directly or acts through upstream/parallel pathways – critical for mechanism deconvolution.

What resistance mechanisms can you model in your platform?

We model both intrinsic and acquired resistance. This includes adaptive pathway activation (e.g., EGFR feedback, MEK reactivation), co-occurring mutations (e.g., STK11, KEAP1), and long-term drug-induced resistance models. We can also test combination strategies to overcome or prevent resistance.

References:

  1. Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019 Nov;575(7781):217–23.
  2. Hong DS, Fakih MG, Strickler JH, et al. KRAS(G12C) inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020 Sep 24;383(13):1207–17.
  3. Cox AD, Fesik SW, Kimmelman AC, et al. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov. 2014 Nov;13(11):828–51.
  4. Huang L, Guo Z, Wang F, et al. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Target Ther. 2021 Nov 15;6(1):386.
* For research use only. Not intended for any clinical use.
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