PO.ET01.06 · 实验与分子治疗
用于评估KRAS抑制剂疗效的患者来源类器官筛选平台
A patient-derived organoid screening platform for evaluating KRAS inhibitor efficacy
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作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
Kirsten大鼠肉瘤（KRAS）基因是一种原癌基因，在结直肠癌（CRC）、胰腺导管腺癌（PDAC）和非小细胞肺癌（NSCLC）中频繁突变，且常与不良临床结局相关。长期以来，KRAS一直被认为是癌症治疗中难以捉摸且历史上"不可成药"的靶点。然而，近期的突破性进展，包括Sotorasib和Adagrasib等KRAS^G12C抑制剂的临床批准，为靶向KRAS^G12C及其他KRAS突变的新型化合物铺平了道路。通过使用与患者相关的临床前模型进行疗效筛选和安全性评估，可加速KRAS抑制剂的开发并降低风险。患者来源类器官（PDO），即HUB Organoids®，是源自正常和恶性上皮组织（包括结肠、胰腺和肺）成体干细胞的先进3D模型。它们重现了原始组织的分子异质性、形态和功能，准确反映患者特异性反应。HUB类器官支持高通量筛选，为测试药物疗效、安全性和耐药机制提供了强大、可扩展的平台。其已表征的基因组和转录组图谱使药物反应能够与分子特征相关联，从而实现患者分层。在本研究中，我们证明了基于PDO的平台可在六周内适用于KRAS抑制剂筛选。使用基于ATP的活力测定，在超过20个携带KRAS突变（G12C、G12D、Q61R、G13C、G12V和G12S）的PDO（CRC、PDAC和NSCLC）组合上测试了八种处于不同临床开发阶段的KRAS抑制剂。各PDO间的反应存在差异。值得注意的是，G12C和G12D突变体分别对KRAS^G12C和KRAS^G12D抑制剂表现出选择性敏感性。通过将这些抑制剂与EGFR抑制剂联用可缓解耐药性，这与EGF驱动的耐药机制一致。此外，KRAS PDO筛选还能评估药物协同作用及正常组织来源PDO的安全性。总之，HUB的KRAS PDO筛选平台为评估KRAS靶向治疗的化合物特异性、效力和联合策略提供了一种省时、突变特异性的方法。
查看英文原文 English abstract
The Kirsten rat sarcoma (KRAS) gene is a proto-oncogene frequently mutated in colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and non-small cell lung cancer (NSCLC), and is often associated with poor clinical outcomes. KRAS has long been considered an elusive and historically “undruggable” target in cancer therapy. However, recent breakthroughs, including the clinical approval of KRAS^G12C inhibitors such as Sotorasib and Adagrasib, have paved the way for novel compounds targeting KRAS^G12C and other KRAS mutations. The development of KRAS inhibitors can be accelerated and de-risked by using patient-relevant preclinical models that enable efficacy screening and safety assessment. Patient-derived organoids (PDOs), or HUB Organoids®, are advanced 3D models derived from adult stem cells of normal and malignant epithelial tissues, including colon, pancreas, and lung. They recapitulate the molecular heterogeneity, morphology, and functionality of the original tissue, accurately reflecting patient-specific responses HUB Organoids support high-throughput screening, providing a powerful, scalable platform for testing drug efficacy, safety, and resistance mechanisms. Their characterized genomic and transcriptomic profiles allow drug responses to be linked to molecular features, enabling patient stratification. In this study We demonstrate the suitability of our PDO-based platform for KRAS inhibitor screening within six weeks. Eight KRAS inhibitors at various clinical development stages were tested on a panel of over 20 PDOs (CRC, PDAC, and NSCLC) harbouring KRAS mutations (G12C, G12D, Q61R, G13C, G12V, and G12S) using an ATP-based viability assay. Responses varied across PDOs. Notably, G12C and G12D mutants showed selective sensitivity to KRAS^G12C and KRAS^G12D inhibitors, respectively. Resistance to these inhibitors was mitigated by combining them with an EGFR inhibitor, consistent with EGF-driven resistance mechanisms. Additionally, KRAS PDO screening enables assessment of drug synergy and safety in normal tissue-derived PDOs. In conclusion, HUB's KRAS PDO screening platform offers a time-efficient, mutation-specific approach for evaluating compound specificity, potency, and combination strategies for KRAS-targeted therapies.
利益披露 Disclosure
M. Derksen, None..
Y. Abouleila, None..
M. M. Costa Silva, None..
G. ten Hag, None..
R. Overmeer, None..
F. Pourfarzad, None..
F. Stavenuiter, None..
R. G. J. Vries, None..
S. F. Boj, None.