CDK8 remodels the tumor microenvironment and promotes resistance to KRAS(G12D) inhibitors and daraxonrasib in PDAC.

CDK8 drives immune evasion and resistance in PDAC by remodeling the tumor microenvironment during KRAS G12D inhibition, with 50% of cases showing resistance.

• Why it matters: Understanding resistance mechanisms is crucial for improving targeted therapies in pancreatic ductal adenocarcinoma, where KRAS mutations are prevalent and difficult to target effectively.
• What they did: Using spatial transcriptomics, single-cell RNA sequencing, and proteomics in mouse models, the study examined immune responses and identified CDK8 as a key mediator of resistance, especially through CXCL2 secretion and FAS inhibition.
• The result: Targeting CDK8 alone or combined with immunotherapy overcame resistance, and increased CDK8 expression was also observed in resistant patient-derived tumors, revealing a common vulnerability in KRAS-driven PDAC.