KRAS mutations drive over 90% of pancreatic ductal adenocarcinoma (PDAC) cases. While inhibitors for $G12C$ mutations are FDA-approved, they benefit only 1% of patients. Most patients harbor $G12D$, $G12V$, or $G12R$ mutations, requiring broader therapeutic strategies.
Recent research presented at AACR RAS 2026 highlights the Optim.AI™ platform. This functional precision medicine tool identifies effective drug combinations based on direct cellular responses rather than genomics.
The Optim.AI™ Methodology
The platform utilizes a multi-step workflow to predict clinical efficacy through ex vivo drug sensitivity testing.
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Cell Isolation: Tumor cells are isolated from biopsies, resections, or fluids like ascites.
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PDO Generation: Cells form short-term patient-derived organoids (PDO).
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Ex vivo Screening: PDOs undergo a 96-hour treatment using a proprietary 11-drug panel.
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Analytics: Optim.AI™ analyzes viability data to rank 2-drug and 3-drug combinations.
Targeted KRAS Inhibitor Synergistic Combinations
The study evaluated four PDAC samples with varying KRAS statuses, including $G12V$ and $G12R$. The platform identified KRAS inhibitor synergistic combinations that outperformed standard-of-care treatments like FOLFIRINOX.
The platform particularly focused on RAS(ON) multi-selective inhibitors like RMC-6236. Optim.AI™ generated response surface maps to visualize drug-drug interactions, distinguishing synergistic pairs from antagonistic ones.
Clinical Implications for PDAC
Functional precision medicine offers a pathway to bypass the limitations of sequencing. By observing how a patient’s own cells react to KRAS G12D and G12V mutation targeting, clinicians can better stratify patients for clinical trials.