CDK8 remodels the tumor microenvironment to resist the therapeutic efficacy of targeted KRAS ^G12D inhibition in pancreatic ductal adenocarcinoma

Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with over 40% of PDAC patients presenting with KRAS ^G12D mutations. The recent development of small molecule inhibitors targeting KRAS ^G12D has enabled targeting of mutant KRAS signaling and suppression of PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained therapeutic efficacy of KRAS ^G12D inhibition and mechanism/s of resistance to KRAS ^G12D suppression remain to be elucidated. Here, we employed spatial transcriptomics, single cell RNA sequencing, and CODEX-based spatial proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRAS ^G12D inhibition with MRTX1133. While KRAS ^G12D inhibition initially increases CD11c ⁺ cells with impactful T cell infiltration within proximity to cancer cells, long-term treatment with MRTX1133 resulted in reversal of the immune responses leading to KRAS ^G12D therapy resistance promoted by CDK8, a multiprotein mediator complex associated kinase. CDK8 imparts resistance in part through induction of downstream CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 by itself and in combination with αCTLA-4 immunotherapy overcomes resistance to KRAS ^G12D inhibition with prolonged survival with translational implications.