A patient-derived organoid screening platform for evaluating KRAS inhibitor efficacy

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.