Evaluation of a Novel Pan-RAS Inhibitor in 3D Bioprinted Tumor Models

Area of Science:

• Oncology
• Pharmacology
• Biotechnology

Background:

• Colorectal cancer (CRC) is a major global health concern, with KRAS mutations present in approximately 40% of cases.
• Current KRAS inhibitors face limitations due to resistance mechanisms and specific mutational requirements.
• Pan-RAS inhibitors, like ADT-007, present a broader therapeutic strategy by targeting multiple RAS isoforms.

Purpose of the Study:

• To evaluate the efficacy and selectivity of the pan-RAS inhibitor ADT-007.
• To assess ADT-007's activity in 3D bioprinted ex vivo slice tissue (BEST) models derived from KRAS-mutant and wild-type (WT) CRC cell lines.
• To benchmark ADT-007 against existing therapeutic agents.

Main Methods:

• Utilized 3D bioprinted ex vivo slice tissue (BEST) models from CRC cell lines.
• Assessed ADT-007 potency and selectivity using high-content imaging and ATP-based luminescence assays.
• Quantified apoptosis induction via Annexin V/propidium iodide staining and flow cytometry.

Main Results:

• ADT-007 demonstrated high potency and selectivity in KRAS-mutant BEST models, reducing tumor burden by over 30% at nanomolar concentrations.
• The drug exhibited superior selectivity with minimal cytotoxicity in WT RAS BEST models.
• Annexin V staining confirmed selective apoptosis induction in KRAS-mutant cells.

Conclusions:

• The selective efficacy of ADT-007 supports further investigation of pan-RAS inhibitors for RAS-driven cancers.
• 3D BEST models are valuable tools for preclinical drug response assessment.
• Clinical validation using patient-derived BEST models is required to confirm ADT-007's therapeutic potential.