CDK8 remodels the tumor microenvironment and promotes resistance to KRAS(G12D) inhibitors and daraxonrasib in PDAC.
Blocking a protein called CDK8 restores cancer drug sensitivity in pancreatic tumors that previously resisted treatment alone.
This MD Anderson study identifies CDK8 as a central mediator of acquired resistance to KRASG12D inhibitors in pancreatic cancer, using multi-modal spatial and single-cell genomics to show that initial immune activation is reversed by CDK8-driven TME remodeling. The finding that CDK8 inhibition can restore sensitivity across multiple KRAS inhibitors (MRTX1133, daraxonrasib, zoldonrasib) positions CDK8 as a rational combination partner as KRASG12D inhibitors advance in clinical trials.
What the study was
- Study design
- preclinical_mechanistic
- Population
- PDAC (pancreatic ductal adenocarcinoma) mouse models and PDX
- Category
- Treatment Innovation
- Maturity
- Exploratory
- Journal
- EMBO Journal
Why it surfaced
KRASG12D inhibitors (daraxonrasib, MRTX1133) are in active clinical trials; CDK8 as a resistance mechanism is a new, actionable target for combination therapy design; multi-omic mechanistic rigor and PDX validation from MD Anderson/Kalluri lab is a high-credibility source; directly relevant to PDAC precision oncology pipeline.
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