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 irreversibly suppresses KRAS-mutant pancreatic cancer, with 90% of cases showing vulnerability independent of KRAS pathways.

• Why it matters: Pancreatic ductal adenocarcinoma (PDAC) driven by KRAS mutations has limited treatment options, and current KRAS-targeted therapies show minimal success, highlighting the need for novel strategies.
• What they did: Researchers combined CRISPR screens, genomic datasets, and pharmacological tests to identify IMPDH2 as a key vulnerability, developing compounds to target it and testing in organoid and mouse models.
• The result: Inhibiting IMPDH2 depletes guanine nucleotides irreversibly, suppressing PDAC growth and enhancing KRAS inhibitor effects, supporting combined targeting of KRAS and nucleotide biosynthesis as a promising therapy.