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Background Over 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.Objective This 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.Results Integrated screens revealed de novo guanine nucleotide biosynthesis (DNGB) as a vulnerability in KRAS-mutant PDAC, with IMPDH2 being the critical gene. Unexpectedly, IMPDH2 expression and activity are not driven by the KRAS vertical pathway. Consequently, IMPDH2 inhibition induces irreversible guanine nucleotide depletion that cannot be compensated for by mutant KRAS. Inducing guanine nucleotide depletion via targeting IMPDH2 for degradation inhibits PDAC and augments KRAS inhibitor efficacy in vitro and in vivo.Conclusions These 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.