Background: Colorectal cancer (CRC) remains a significant global health burden, with KRAS mutations driving ~40% of cases. The efficacy of recently approved, mutant-specific KRAS inhibitors is limited by mutational status as well as 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 ex vivo slice tissue (BEST) generated from KRAS-mutant and RAS wild-type (WT) CRC cell lines.Methods: Potency and selectivity of ADT-007 were benchmarked against bortezomib (proteasome inhibitor) and YM155 (survivin inhibitor) using high-content imaging and ATP-based luminescence assays. Apoptosis induction was assessed with Annexin V/propidium iodide and flow cytometry.Results: ADT-007 exhibited high potency and selectivity in KRAS-mutant BEST, reducing tumor burdens >30% at nanomolar concentrations, and demonstrated superior selectivity with minimal cytotoxicity in WT RAS BEST. Annexin V staining confirmed selective induction of apoptosis in KRAS-mutant cells.Conclusions: The selective potency and specificity of ADT-007 warrant further investigation of pan-RAS inhibitors for treating RAS-driven cancers. This study also underscores the translational utility of 3D BEST models for preclinical drug response assessment. Further validation in patient-derived BEST is necessary to evaluate the potential of ADT-007 in clinical settings.
背景：结直肠癌（CRC）作为全球重大健康负担，其中约40%的病例由KRAS基因突变驱动。近期获批的突变特异性KRAS抑制剂因突变状态及内在与适应性耐药机制而疗效受限。泛RAS抑制剂（如ADT-007）通过靶向多种RAS亚型展现出更广阔的治疗潜力。本研究在基于KRAS突变型与RAS野生型（WT）CRC细胞系构建的3D生物打印离体切片组织（BEST）模型中评估ADT-007的疗效。 方法：采用高内涵成像技术与ATP发光法检测，以硼替佐米（蛋白酶体抑制剂）和YM155（生存素抑制剂）为参照，评估ADT-007的效价与选择性。通过膜联蛋白V/碘化丙啶染色及流式细胞术检测细胞凋亡诱导情况。 结果：ADT-007在KRAS突变型BEST模型中显示出高效价与选择性，纳摩尔浓度下即可使肿瘤负荷降低超过30%，且在WT RAS BEST模型中表现出卓越的选择性及极低的细胞毒性。膜联蛋白V染色证实该药物能选择性诱导KRAS突变细胞发生凋亡。 结论：ADT-007的选择性效价与特异性支持对泛RAS抑制剂治疗RAS驱动型癌症的进一步研究。本研究同时凸显了3D BEST模型在临床前药物反应评估中的转化应用价值。需在患者来源的BEST模型中进行进一步验证，以评估ADT-007在临床环境中的应用潜力。
Evaluation of a Novel Pan-RAS Inhibitor in 3D Bioprinted Tumor Models
肿瘤(癌症)患者之家