CDK8 remodels the tumor microenvironment to resist the therapeutic efficacy of targeted KRASG12D 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 KRASG12D mutations. The recent development of small molecule inhibitors targeting KRASG12D, has enabled effective targeting of mutant KRAS signaling and suppression of PDAC; however, the contribution of the tumor microenvironment (TME) to the therapeutic efficacy of KRASG12D inhibition and mechanism/s of resistance to KRASG12D suppression remain to be elucidated. Here, we employed spatial transcriptomics and CODEX-based spatial proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRASG12D inhibition with MRTX1133. MRTX1133 treatment was associated with increased CD11c+ cells, T cells, and tumor-restraining fibroblasts within proximity to cancer cells, suggesting that antigen presentation and remodeling of the local microenvironment is associated with an effective response to KRASG12D inhibition. In the context of emergence of MRTX1133 therapy resistance, CDK8, a multiprotein mediator complex associated kinase, was identified as a mediator of 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 in combination with aCTLA-4 immunotherapy overcomes resistance to small molecule mediated targeted KRASG12D inhibition with prolonged survival of mice with PDAC.