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

backgroundOver 90% pancreatic cancers harbour activating kirsten rat sarcoma viral oncogene homolog (KRAS）mutations. However, monotherapies targeting the KRAS vertical pathway, with recently developed KRAS inhibitors or rapidly accelerated fibrosarcoma (RAF)/MEK/ERK inhibitors, have demonstrated limited clinical benefit. Therefore, there is an urgent need to identify novel therapeutic targets and combination strategies with KRAS inhibition.

objectiveThis study aims to identify pharmaceutical targets whose inhibition suppresses pancreatic ductal adenocarcinoma (PDAC) or potentiates KRAS inhibition, focusing on molecular vulnerabilities specific to KRAS-mutant PDAC. DESIGNS: We integrated genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 (CRISPR-associated Protein 9) dropout screens, large-scale genomic dependency datasets and pharmacological screens to identify molecular vulnerabilities in KRAS-mutant PDAC. Conditional knockout mouse models were used to assess the essentiality of candidate genes in pancreatic cancer. RNA sequencing, metabolomics/proteomics analysis and stable isotopic tracing were employed to investigate mechanisms underlying inosine monophosphate dehydrogenase 2 (IMPDH2) vulnerability. Additionally, proteolysis-targeting chimaera compounds targeting IMPDH2 were developed and evaluated in patient-derived organoid and xenograft models.

resultsIntegrated screens revealed de novo guanine nucleotide biosynthesis (DNGB) as a vulnerability in KRAS-mutant PDAC, with

conclusionsThese findings provide a rationale for developing combination therapies targeting KRAS and DNGB, highlighting the potential of purine nucleotide imbalance as a biomarker to guide the application of these therapies.