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Updated: May 23, 2025
Generation of High-Throughput Three-Dimensional Tumor Spheroids for Drug Screening
Published on: September 5, 2018
Potency and selectivity of a novel pan-RAS inhibitor in 3D bioprinted organoid tumor models
Background:
Colorectal cancer (CRC) remains a significant global health burden, with KRAS mutations driving ∼40% of cases. Efficacy of recently approved, mutant-specific KRAS inhibitors is limited by intrinsic and adaptive resistance mechanisms. Pan-RAS inhibitors, such as ADT-007, offer broader therapeutic potential by targeting multiple RAS isoforms. Here, we evaluate ADT-007 in 3D bioprinted organoid tumors (BOTs) generated from KRAS-mutant and RAS wild-type (WT) CRC cell lines.
Methods:
Potency and selectivity of ADT-007 were compared to bortezomib, a proteasome inhibitor, and YM155, a survivin inhibitor, using high-content imaging and ATP-based luminescence assays. Mechanistic studies assessed impact on RAS activation and downstream signaling.
Results:
ADT-007 exhibited high potency and selectivity in KRAS-mutant BOTs, reducing tumor burdens >30% at nanomolar concentrations, and demonstrated superior selectivity over bortezomib and YM155 with minimal cytotoxicity in RAS-WT BOTs. Mechanistic analysis confirmed ADT-007 inhibited RAS activation and downstream signaling, leading to selective apoptosis induction in KRAS-mutant CRC cells.
Conclusions:
The selective potency and specificity of ADT-007 warrants further investigation of pan-RAS inhibitors for treating RAS-driven cancers. This study also underscores the translational utility of 3D BOT models for preclinical drug response assessment. Further validation in patient-derived BOTs is necessary to evaluate potential of ADT-007 in clinical settings.
Insights
Pan-RAS inhibitor ADT-007 shows potent and selective efficacy against KRAS-mutant colorectal cancer (CRC) organoids. This study highlights ADT-007
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Colorectal cancer (CRC) is a major health concern, with KRAS mutations present in approximately 40% of cases.
- Current KRAS inhibitors face limitations due to resistance mechanisms.
- Pan-RAS inhibitors like ADT-007 target multiple RAS isoforms, offering broader therapeutic potential.
Purpose of the Study:
- To evaluate the efficacy and selectivity of the pan-RAS inhibitor ADT-007.
- To assess ADT-007 in 3D bioprinted organoid tumors (BOTs) derived from KRAS-mutant and wild-type (WT) CRC cell lines.
- To compare ADT-007 with existing inhibitors like bortezomib and YM155.
Main Methods:
- Utilized 3D bioprinted organoid tumors (BOTs) from CRC cell lines.
- Employed high-content imaging and ATP-based luminescence assays to assess potency and selectivity.
- Conducted mechanistic studies to analyze RAS activation and downstream signaling pathways.
Main Results:
- ADT-007 demonstrated high potency and selectivity in KRAS-mutant CRC BOTs, reducing tumor burden by over 30% at nanomolar concentrations.
- ADT-007 showed superior selectivity compared to bortezomib and YM155, with minimal cytotoxicity in RAS-WT BOTs.
- Mechanistic studies confirmed ADT-007's inhibition of RAS activation and downstream signaling, inducing selective apoptosis in KRAS-mutant CRC cells.
Conclusions:
- The selective efficacy of ADT-007 supports further investigation of pan-RAS inhibitors for RAS-driven cancers.
- 3D BOT models are valuable tools for preclinical drug response assessment.
- Clinical validation in patient-derived BOTs is required to determine ADT-007's therapeutic potential.
