Integrated screens reveal that guanine nucleotide depletion, which is irreversible via targeting IMPDH2, inhibits pancreatic cancer and potentiates KRAS inhibition.

Guanine nucleotide depletion via IMPDH2 inhibition suppresses pancreatic cancer and enhances KRAS inhibitor efficacy, with depletion being irreversible and independent of KRAS pathways.

• Why it matters: Pancreatic cancers with KRAS mutations have limited response to existing monotherapies targeting KRAS or its pathway, creating a critical need for new combination strategies.
• What they did: The study used integrated CRISPR/Cas9 screens, genomic datasets, and pharmacological tests to identify IMPDH2 as essential for KRAS-mutant PDAC, and developed compounds to target IMPDH2 in patient-derived models.
• The result: Inhibiting IMPDH2 causes irreversible guanine nucleotide depletion that cannot be rescued by mutant KRAS, leading to suppressed tumor growth and improved KRAS inhibitor responses, supporting combined therapy development.